JP2024504267A - Treatment method using LOU064 - Google Patents

Abstract

The present disclosure provides a method of treating and/or preventing an IgE-induced allergic response to one or more allergens, preferably food allergens, in a subject having such a disease or condition, comprising: of LOU064.

Description

The present invention relates to BTK inhibitors, such as LOU064, or a pharmaceutically acceptable salt or polymorph thereof, for use in the effective suppression of IgE-induced allergic responses to one or more allergens.

Food allergies affect millions of people of all ages in all countries, and the rapidly increasing prevalence suggests that it is an emerging public health priority (Warren et al 2020). The fundamental cause of food allergy is that allergen-specific IgE is synthesized in response to allergen exposure and is transmitted through its Fc region to the high-affinity receptor for IgE (FcεRI receptor) on the surface membrane of mast cells and basophils. ) is involved in the immune system. (Sampson et al 2006). Food allergies affect nearly 10% of people worldwide, and consistent epidemiological trends have been observed across North America, Europe, Asia and Australia; the most common allergens are peanuts, nuts, seafood, eggs, milk, wheat, soybeans, and seeds (Warren et al 2020, Sicherer and Sampson 2017). Allergies to peanuts, nuts, and seafood are usually lifelong (Jones and Burks 2017, Sicherer and Sampson 2017). Furthermore, one-third to one-half of food allergy patients, including adults, are likely to be allergic to two or more foods (Gupta et al 2011, Gupta et al 2019). Anaphylaxis is a sometimes life-threatening systemic allergic reaction to substances such as food, drugs, or stinging insect venom. Despite efforts to reduce allergies to these substances using immunotherapy, the prevalence of anaphylaxis is increasing (Lieberman P. et al., Ann Allergy Asthma Immunol. 2006;97(5):596- 602). Unfortunately, it is often fatal even with immediate comprehensive medical treatment (J. Allergy Clin. Immunol. 2020;145(4):1082). There are no known treatments that can prevent IgE-mediated anaphylaxis.

The IgE pathway plays a central role in the pathogenesis of most allergic diseases, including food allergy, drug allergy, allergic rhinitis, asthma, and chronic urticaria. When allergen-specific IgE binds to allergens and cross-links high-affinity receptors (FcεRI) on the surface of mast cells and basophils, activated signaling cascades trigger signs and symptoms. triggers the release of many allergy mediators, including histamine, prostaglandins, leukotrienes, and cytokines, which are involved in

Until now, treatment of allergic diseases has largely relied on blockade of specific mediators (eg, with antihistamines or leukotriene receptor antagonists) and/or broad immunosuppression with corticosteroids.

Currently, there is no effective treatment that can prevent anaphylaxis, and the mainstay of treatment is prevention by avoiding triggers. However, as strict avoidance is not always possible, especially in the case of food allergies, standard treatment consists of early detection of signs and symptoms and the use of intramuscularly injected epinephrine after a reaction occurs. Become. In contrast, patients are intentionally exposed to allergens, such as during skin testing, allergen immunotherapy (IT), and drug desensitization (all procedures carry the risk of severe systemic reactions). There are situations where this happens. Desensitization to allergens, such as food allergens or drugs, is costly and labor intensive as these typically require hospitalization of the patient due to the risk of potentially life-threatening reactions.

Several immunizations have been tested for food allergies, including oral immunotherapy (OIT), sublingual immunotherapy (SLIT), transdermal immunotherapy (EPIT), and OIT combined with an anti-IgE monoclonal antibody (omalizumab). Therapy exists. However, efficacy and safety were only demonstrated in one Phase III trial for peanut allergy. Additionally, there were only three randomized controlled trials of the omalizumab-OIT combination, and these were low-powered, single-center trials; in these trials, the level of evidence was low. Trials with long-term follow-up are rare, and therefore clinical tolerability is unclear and remains unclear (Shoichiro T et al. EMJ. 2019;4[4]:63-70).

Currently, there is only one approved oral immunotherapy (OIT) (Palforzia™) for peanut allergy patients.

BTK is an essential kinase for FcεRI-mediated signal transduction in human mast cells and basophils. Because it is also important for B cell maturation, BTK has been targeted pharmacologically for the treatment of B cell malignancies. There are currently three FDA-approved BTK inhibitors (BTKis) in the United States. Ibrutinib (trade name Imbruvica®; Pharmacyclics, and AbbVie), acalabrutinib (Calquence®; Acerta and AstraZeneca), and zanubrutinib (Brukinsa®; BeiGene) are all BT Oral covalent bond small It is a molecular inhibitor.

Additionally, several BTK inhibitors (BTKis) are in clinical trials for the treatment of autoimmune diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), and systemic lupus erythematosus (SLE). For example, acalabrutinib and zanubrutinib and the novel compounds ONO-4059 (tirabrutinib), HM71224 (posertinib) and ABBV-105 (upadacitinib) are effective for treating B-cell malignancies and/or autoimmune diseases such as RA, Sjögren's syndrome (SjS) and SLE. are currently being tested for their effectiveness in Additionally, evobrutinib, trebrutinib and fenebrutinib are in Phase III trials in MS patients, olelabrutinib was tested in a Phase II trial, and BIIB091 was tested in a Phase I trial for efficacy in the treatment of MS. .

The study also demonstrated the ability of ibrutinib to reduce or eliminate skin prick test reactivity to air allergens and foods in allergic patients (Dispenza et al. J. Allergy Clin Immunol. 2018;141(5):1914-1916.e7). and skin tests returned to baseline 1 week after stopping ibrutinib, suggesting a short duration of efficacy (2021). However, it is unclear whether the inhibitory effects seen in skin prick tests translate to inhibitory effects in organs other than the skin. The degree of penetration of BTKis into the various tissues where mast cells reside is unknown. Although ibrutinib has been demonstrated to have rapid efficacy in preventing IgE-mediated activation of circulating basophils, It is unclear whether IgE-mediated activation of resident mast cells can be sufficiently inhibited.

Despite suggestions that BTK inhibitors may be used to prevent and/or treat allergic reactions to plants, BTK inhibitors have been shown to suppress clinically relevant allergic reactions and/or prevent anaphylaxis in humans. It has not yet been shown that Although acalabrutinib is currently in Phase II trials in the prevention of allergic reactions to peanut allergens in adults with peanut allergies, clinical efficacy data for BTK inhibitors in the context of food allergy have not previously been reported. .

Furthermore, due to the lack of selectivity of some of the more previously developed BTK inhibitors (e.g. acalabrutinib, ibrutinib), these BTK inhibitors are particularly useful for long-term/chronic and indications requiring safe use. may not be suitable for non-malignant indications, for the treatment of children and/or in the pediatric or adolescent population. The most common side effects of currently approved BTK inhibitors include nausea, diarrhea, rash, infections, cytopenias, bleeding and arrhythmias. Notably, the long-term toxicity profile of ibrutinib, a first-in-class inhibitor, is well characterized and includes clinically significant occurrences of arrhythmias, bleeding, infections, diarrhea, arthralgia, and hypertension. . Acalabrutinib, an early second-generation BTKi to gain approval from the US Food and Drug Administration, demonstrates improved kinase selectivity for BTKs but is associated with general (Hematology Am Soc Hematol Educ Program. 2020 Dec 4; 2020(1):336-345).

Although long-term safety data are not available for the BTK inhibitors currently in development, the available safety data for fenebrutinib indicate that the biggest hurdle that BTK inhibitors can face is that side effects are tolerable during chronic use. It may suggest that it is possible or not. For example, the major event of note in the Phase IIa trial of fenebrutinib was a transient grade 3 increase in ALT and/or AST in 8.3% and 6.3% of subjects in the high-dose treatment arm. . Some of the side effects already observed for some BTKis may limit their use to treat or prevent non-malignant indications, especially if long-term administration may be required. Additionally, none of the FDA-approved BTK inhibitors have been approved in children and adolescents. Therefore, until safety data in children are available, it is unclear whether BTK inhibitors are a viable option for use in the treatment or prevention of IgE-induced allergic reactions in children.

Currently limited treatment options due to rising morbidity (including allergies to multiple foods), potentially life-threatening consequences, inability to avoid food alone to confer protection, and Because of the lifelong burden of disease, there is a great medical need to develop new and safe treatments for food allergies.

Passive cutaneous anaphylaxis (PCA) in mice: LOU064 inhibits skin edema. BTK occupancy in the spleen of BALB/c mice 2.5 hours after administration. Reverse passive Arthus (RPA) response in mouse skin: LOU064 inhibits skin swelling. BTK occupancy in the spleen of C57B16 mice 5 hours after administration. Time-dependent pharmacological effects of LOU064 on skin swelling. Comparison of time-dependent BTK occupancy in the spleen and lungs for pharmacological inhibition of skin swelling after a single dose of 30 mg/kg LOU064. 1% w/v OVA or saline (aerosol, days 21-24) and PBS at 16 hours and PBS at 16 hours (intrathecal (i.t.) groups 1 and 2) or LOU064 (10 mg/Kg and 30 mg/kg, orally (p.o.), bronchopulmonary after treatment with (b.i.d.) or vehicle (10 mL/Kg, orally (p.o.), twice a day (b.i.d.)) Effect on the total number of cells in the alveolar lavage fluid (BALF). BALF was collected 24 hours after OVA challenge. 1% w/v OVA or saline (aerosol, days 21-24) and PBS at 16 hours and PBS at 16 hours (intrathecal (i.t.) groups 1 and 2) or LOU064 (10 mg/Kg and 30 mg/kg, orally (p.o.), bronchopulmonary after treatment with (b.i.d.) or vehicle (10 mL/Kg, orally (p.o.), twice a day (b.i.d.)) Effect on the number of eosinophils in the alveolar lavage fluid (BALF). BALF was collected 24 hours after OVA challenge. 1% w/v OVA or saline (aerosol, days 21-24) and PBS at 16 hours and PBS at 16 hours (intrathecal (i.t.) groups 1 and 2) or LOU064 (10 mg/kg and 30 mg/kg, orally (p.o.), bronchoalveolar after treatment with twice daily (b.i.d.) or vehicle (10 mL/Kg, orally (p.o.), twice daily (b.i.d.)) Effect on the number of neutrophils in the lavage fluid (BALF). BALF was collected 24 hours after OVA challenge. 1% w/v OVA or saline (aerosol, days 21-24) and PBS at 16 hours and PBS at 16 hours (intrathecal (i.t.) groups 1 and 2) or LOU064 (10 mg/kg and 30 mg/kg, orally (p.o.), bronchoalveolar after treatment with twice daily (b.i.d.) or vehicle (10 mL/Kg, orally (p.o.), twice daily (b.i.d.)) Effect on the number of macrophages in the lavage fluid (BALF). BALF was collected 24 hours after OVA challenge. 1% w/v OVA or saline (aerosol, days 21-24) and PBS at 16 hours and PBS at 16 hours (intrathecal (i.t.) groups 1 and 2) or LOU064 (10 mg/Kg and 30 mg/kg, orally (p.o.), bronchoalveolar after treatment with twice daily (b.i.d.) or vehicle (10 mL/Kg, orally (p.o.), twice daily (b.i.d.)) Effect on the number of lymphocytes in the lavage fluid (BALF). BALF was collected 24 hours after OVA challenge. Preferred particle size distribution of nanosized LOU064. Simulation of splenic BTK occupancy at steady state. (A) Trough of BTK occupancy at steady state over 24 hours. Graph showing the median prediction as points and a vertical line indicating the 95% prediction interval. (B) Average of BTK occupancy over 24 hours at steady state. Graph showing the median prediction as points and a vertical line indicating the 95% prediction interval.

The problem underlying the invention is an IgE-induced allergic reaction, such as a food, drug or poison allergic reaction, in particular an IgE-induced allergic reaction to one or more allergens, such as a food allergen, more particularly an IgE-induced anaphylactic reaction, such as an IgE-induced allergic reaction The aim is to provide safe and effective treatment or prevention of cancer. In particular, it is an object of the present invention to provide a safe and effective long-term treatment or prevention of IgE-induced food allergic reactions, such as anaphylactic reactions.

The present invention therefore provides BTK inhibitors, e.g. reversible or irreversible BTK, for use in the treatment and/or prevention of IgE-induced allergic reactions, e.g. Regarding inhibitors. In particular, the present invention provides a selective drug that is safe and suitable for long-term use (i.e. chronic use) in the treatment and/or prevention of IgE-induced allergic reactions, such as food, drug or poison allergic reactions, more particularly food allergic reactions. Regarding BTK inhibitors. Particularly useful in the present invention are BTK inhibitors that are selective for other structurally similar Tec family kinases such as BMX, ITK and TXK. More particularly useful in the invention are BTK inhibitors that are selective for BTK over tec (eg, at least 10-fold, at least 20-fold, at least 30-fold BTK/Tec selectivity).

Another object of the present invention is to provide improved treatment and/or prevention of IgE-induced allergic reactions, such as food, drug, or poison allergic reactions, more particularly food allergic reactions. One aspect of the invention is to provide improved prevention of IgE-induced anaphylaxis induced by, for example, one or a mixture of food allergens. For example, one object of the present invention is to provide a method that is more effective and/or safer than treatment with other BTK inhibitors (e.g., less selective BTK inhibitors), in particular more effective and/or safer than treatment with acalabrutinib, or ibrutinib. It is an object of the present invention to provide a safer treatment for the treatment or prevention of IgE-induced allergies. It is also an object of the present invention to provide a treatment and/or prevention of IgE-induced allergic reactions, in particular food allergic reactions, that is more effective, safer and/or more convenient than treatment with anti-IgE monoclonal therapy. be. In particular, it is an object of the present invention to provide an IgE-induced allergy that has a faster onset of action (e.g. less than 4 weeks, less than 2 weeks or less than 1 week) compared to anti-IgE monoclonal therapies which take 8-12 weeks to develop. To provide treatment and/or prevention of reactions, and to provide treatments that are more conveniently administered at home and do not require the use of a medical facility.

Thus, a method for preventing or treating an IgE-induced allergic reaction, such as a food, drug, or toxin allergic reaction, such as an anaphylactic reaction, more particularly to one or more food allergens (e.g. peanut, nut, milk, wheat, soy, egg, etc.). A method of preventing or treating an IgE-induced allergic reaction to sesame seeds, seafood, or a mixture thereof, comprising administering a therapeutically effective dose of LOU064 to a subject in need thereof: Disclosed herein.

Another aspect of the invention is to treat or treat IgE-induced food allergic reactions to one or more allergens (e.g., food allergens such as peanut, nut, milk, wheat, soy, egg, sesame, seafood, or mixtures thereof). It relates to an irreversible BTK inhibitor, such as LOU064 or a pharmaceutically acceptable salt thereof, for the prevention, preferably for the prevention of IgE-induced food allergic reactions to one or more allergens.

A further subject of the invention is a method for the manufacture of a medicament for use in the above-mentioned treatments.

Further aspects, advantageous features and preferred embodiments of the invention, summarized in embodiments E1 to E39 below, each serve alone or in combination to solve the objects of the invention:

E1. A method of treating or preventing an IgE-induced allergic response to one or more allergens (e.g., a drug, poison, or food allergen) in a subject in need thereof, the method comprising: a therapeutically effective dose of a selective BTK inhibitor, e.g. A method comprising administering LOU064 to a patient.

E2. The method of E1, wherein the one or more allergens include or are food allergens.

E3. The method according to E2, wherein the food allergen is selected from peanuts, nuts, milk, wheat, eggs, soybeans, sesame, seafood, especially peanuts.

E4. The method of E1, E2, or E3, wherein the therapeutically effective dose of LOU064 is about 20 mg to about 200 mg daily.

E5. The method of E4, wherein the therapeutically effective dose of LOU064 is about 10 mg twice a day to about 100 mg twice a day.

E6. The method of E5, wherein the therapeutically effective dose of LOU064 is about 10 mg twice daily.

E7. The method of E5, wherein the therapeutically effective dose of LOU064 is about 25 mg twice daily.

E8. The method of E5, wherein the therapeutically effective dose of LOU064 is about 100 mg twice daily.

E9. The method according to any one of E1 to E8, wherein LOU064 is administered for a short period of time, such as less than 6 months, preferably less than 3 months or less than 1 month.

E10. The method according to E9, wherein LOU064 is administered for up to 18 weeks, such as 4, 10, 12, 16 or 18 weeks.

E11. The method according to any one of E1 to E8, wherein LOU064 is administered for an extended period of time, eg for more than 6 months, eg for more than 1 year, preferably for more than 1 year.

E12. The method of any one of E1-E11, wherein LOU064 is administered as a monotherapy.

E13. The method according to any one of E1-E12, wherein LOU064 is not administered simultaneously with a strong inhibitor of CYP3A, such as a strong inhibitor of CYP3A4.

E14. The method of any one of E1-E11 and E13, wherein LOU064 is co-administered with a therapeutic agent.

E15. LOU064 is co-administered with corticosteroids and/or immunosuppressants (e.g. inhaled corticosteroids), leukotriene receptor antagonists (LTRA), short-acting beta agonists (SABA) or long-acting beta agonists (LABA) The method according to E14.

E16. According to any one of claims E1 to E11 and E13, wherein LOU064 is co-administered with oral immunotherapy (OIT), sublingual immunotherapy (SLIT), transcutaneous immunotherapy (EPIT), preferably with OIT. the method of.

E17. The method according to E16, wherein LOU064 is oral immunotherapy (OIT), sublingual immunotherapy (SLIT), transdermal immunotherapy (EPIT), preferably an adjunct to OIT.

E18. The method according to E16 or E17, wherein the oral immunotherapy is peanut protein (eg Palforzia).

E19. The method of any one of E16-E18, wherein LOU064 is administered starting at least 2 days (eg, at least 2-14 days) before administration of the oral immunotherapy.

E20. The method of E19, wherein LOU064 is administered during the titration phase of immunotherapy treatment.

E21. The method according to any one of E1-E20, wherein the method is the prevention of IgE-induced allergic reactions.

E22. The method according to any one of E1 to E21 for preventing anaphylaxis after accidental exposure to any allergen or mixture thereof (eg food allergen).

E23. The method according to E21 or E22, wherein LOU064 achieves maximum protection after a minimum of 2 days (eg, 2-14 days, preferably 2-7 days) after treatment.

E24. Patients meet the following criteria:
(a) Male and female patients, 2 years of age or older (eg 2-5 years, or 6-11 years, 12-17 years, or 18-55 years);
(b) a confirmed history of allergies to foods including, but not limited to, peanuts, nuts, wheat, eggs, milk, soy, seafood;
(c) positive allergen-specific IgE (e.g., peanut sIgE ≧6 kUA/L at screening); and (d) positive skin prick test for the allergen to which the patient is allergic (e.g., compared to negative control). , defined as a wheal with an average diameter (longest diameter and midpoint orthogonal diameter) ≥4 mm)
The method according to any one of E1-E23, selected according to one or more of:

E25. The method according to any of E1 to E24, wherein the patient is an adult patient (18 years or older) or an adolescent (12 to 17 years old).

E26. The method according to any of E1 to E24, wherein the patient is a child aged 2 to 11 years, such as 2 to 5 years or 6 to 11 years.

E27. At least one of the following applies:
up to 4 weeks (e.g. 1 week, or 2 weeks, or 3 weeks or 4 weeks) after treatment with LOU064;
a. At least 90% of treated patients do not exhibit allergic reactions upon dietary loading of 600 mg peanut protein;
b. At least 90% of treated patients do not exhibit allergic reactions upon dietary loading of 1000 mg peanut protein;
c. The method according to any one of E1 to E26, wherein at least 80% of the treated patients do not exhibit an allergic reaction upon a dietary challenge of 3000 mg of peanut protein.

E28. The method of any one of E1-E27, wherein the patient achieves a reduction from baseline in total domain score FAQLQ of 0.45 to 0.5.

E29. The method of any one of E1-E28, wherein the patient achieves a reduction from baseline in total domain score FAIM.

E30. The observed difference in response rate between treated and untreated patients in a double-blind, placebo-controlled food challenge of 600 mg of allergen (e.g., peanut allergen) is greater than 35%, where the response rate is defined as being less than or equal to a mild response to an oral food challenge of 600 mg.

E31. By week 12 or week 24 of treatment, levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lipase have decreased by 10% compared to baseline levels at the beginning of treatment. The method according to any one of E1 to E30, wherein the method does not change by more than

E32. The method according to any one of E1-E31, wherein LOU064 is administered in the form of a suitable oral pharmaceutical formulation comprising nanosized particles of LOU064.

E33. The method according to any one of E1-E32, wherein the LOU064 is administered in the form of a suitable oral pharmaceutical formulation comprising nanosized particles of LOU064 having an average particle size of about 50 nm to about 750 nm as measured by PCS. .

E34. The method of any one of E1-E33, wherein LOU064 is administered in the form of a suitable oral pharmaceutical formulation comprising LOU064 and a binder in a weight ratio of about 2:1.

E35. The method of any one of E1-E34, wherein LOU064 is administered in the form of a suitable oral pharmaceutical formulation comprising LOU064, binder and surfactant in a weight ratio of about 2:1:0.08.

E36. The method according to any one of E1-E33, wherein LOU064 is administered in the form of a suitable oral pharmaceutical formulation comprising LOU064 and a binder in a weight ratio of about 1:1.

E37. The method of any of E1-E33 and E36, wherein LOU064 is administered in the form of a suitable oral pharmaceutical formulation comprising LOU064, a binder and a surfactant in a weight ratio of about 1:1:0.05.

E38. The method according to any one of E1 to E37, wherein LOU064 is administered in the form of a suitable oral pharmaceutical formulation comprising LOU064, polyvinylpyrrolidone-vinyl acetate copolymer as a binder and sodium lauryl sulfate as a surfactant.

E39. When LOU064 is measured at a temperature of about 25° C. and an X-ray wavelength, λ, of 1.5405 Å, it has 7.8 ± 0.2° 2θ, 9.2 ± 0.2° 2θ, 12.0 ± 0. 2°2θ, 13.6±0.2°2θ, 15.6±0.2°2θ, 16.0±0.2°2θ, 17.8±0.2°2θ, 18.3±0. 2°2θ, 18.7±0.2°2θ, 19.2±0.2°2θ, 19.9±0.2°2θ, 22.1±0.2°2θ, 23.4±0. 2°2θ, 23.9±0.2°2θ, 24.8±0.2°2θ, 25.2±0.2°2θ, 25.5±0.2°2θ, 27.2±0. 2° 2θ, and 29.6 ± 0.2° 2θ, characterized by an X-ray powder diffraction pattern containing one or more representative peaks in 2θ , E1 to E38.

Definitions As used herein, Bruton's tyrosine kinase (BTK) is a member of the cytoplasmic tyrosine kinase and TEC kinase family. BTK is expressed in selected cells of the adaptive and innate immune system, including B cells, macrophages, mast cells/basophils, and platelets. BTK is essential for signal transduction through Fcε receptors (FcεR1 for IgE) and activated Fcγ receptors (FcγR for IgG), as well as B cell antigen receptors (BCR) and BTK inhibitors. BTK inhibitors such as ibrutinib have been approved for the treatment of B cell malignancies (Hendriks et al 2014). Recently, inhibition of BTK was demonstrated to result in inhibition of mast cell and basophil activation/degranulation in vitro and reduction in wheal size in skin prick tests by patients suffering from IgE-mediated allergies (Smiljkovic et al. al 2017; Regan et al 2017; Dispenza et al 2018). Therefore, inhibition of BTK may be useful for treating various autoimmune and chronic inflammatory diseases, including rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, chronic urticaria, atopic dermatitis, asthma, and primary Sjögren's syndrome. It is an attractive therapeutic concept (Tan et al 2013; Whang and Chang 2014). Examples of BTK inhibitors include non-covalent, reversible BTK inhibitors such as fenebrutinib, and non-covalent, irreversible inhibitors of BTK such as evobrutinib, trebrutinib, rilzabrutinib, tirabrutinib, branebrutinib, orelabrutinib and remibrutinib (LOU064). specific inhibitors.

As used herein, IgE refers to immunoglobulin E.

The term "comprising" includes "including" as well as "consisting"; for example, a composition "comprising" X may consist only of X; Or it may include something additional, for example X+Y.

The term "about" in relation to a numerical value x means, for example, +/-10%. When used before a numerical range or list of numbers, the term "about" applies to each numerical value in the series; for example, the phrase "about 1 to 5" is interpreted as "about 1 to about 5." or, for example, the phrase "about 1, 2, 3, 4" should be construed as "about 1, about 2, about 3, about 4, etc."

As used herein, the term "pharmaceutically acceptable" means that there is no risk of undue toxicity, irritation, allergic reactions, or other Refers to compounds, materials, compositions, and/or dosage forms that are suitable for use in contact with human and animal tissues without problems or complications.

The term "salt" or "salts" refers to the acid addition salts of the compounds of the present invention. "Salts" include, in particular, "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salt" refers to salts that retain the biological effects and properties of the compounds of the invention and are typically not biologically or otherwise deleterious. In many cases, the compounds of the invention are capable of forming acid salts due to the presence of an amino group thereon. Examples of salts are those disclosed in WO 2020/234779 and WO 2015/079417, which are incorporated herein by reference.

As used herein, the term "polymorph" refers to crystalline forms that have the same chemical composition but different spatial arrangement of the molecules, atoms, and/or ions that form the crystal. The crystalline form of LOU064 is disclosed in WO 2020/234779, which is incorporated herein by reference.

The phrase "administering" in the context of a compound, eg, LOU064, is used to refer to the delivery of that compound to a subject by any route, preferably oral administration.

As used herein, the term "therapeutically effective amount or dose" of a compound of the present disclosure (i.e., a compound of formula (I) or a pharmaceutically acceptable salt or polymorph thereof) induce a biological or medical response, e.g., reduce or inhibit enzyme or protein activity, or ameliorate symptoms, alleviate pathology, slow or delay disease progression, or cure disease. Refers to an amount of a compound of the present disclosure, such as to prevent a therapeutically effective dosage of a compound, pharmaceutical composition, or combination thereof, depending on the patient's species, weight, age, sex, and individual medical condition, treatment The frequency of administration will vary depending on the compound used and the particular condition being treated or prevented.

As used herein, the term "pharmaceutically acceptable carrier" is defined as known to those of skill in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329), any solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterials, antifungals), isotonic agents, absorption delaying agents, salts, preservatives, drugs. Including stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, etc., and combinations thereof. Any conventional carrier is contemplated for its use in therapeutic or pharmaceutical compositions, provided that it is not incompatible with the active ingredient.

The term "therapy" or "treating" refers to the administration of a BTK inhibitor, such as LOU064 or a pharmaceutically acceptable salt thereof, to a subject (preferably a human) or a tissue or cell line isolated from a subject. , or the application or administration of a pharmaceutical composition comprising LOU064 or a pharmaceutically acceptable salt thereof, wherein the subject is suffering from a particular disease (e.g., IgE-induced food allergy), disease have associated symptoms (e.g. IgE-induced food allergic reactions) or a predisposition to developing a disease (if applicable), the purpose of which is to cure one or more symptoms of the disease (if applicable); To reduce the severity, to alleviate or ameliorate such symptoms, to ameliorate the disease, to reduce or ameliorate any associated symptoms of the disease or the tendency to develop the disease. The term "treatment" or "treating" includes treating a subject suspected of having a disease as well as a subject who is sick or diagnosed as suffering from a disease or condition.

As used herein, the terms "prophylaxis," "prophylaxis," and "prevention" of a disease or disorder (IgE-induced food allergy) refer to prophylactic treatment of the disease or disorder; Refers to delaying the onset or progression and/or suppressing (eg, suppressing IgE-induced food allergic reactions). The term "prevention" refers to reducing the sensitivity of a patient subject to an allergen (i.e., increasing the threshold of sensitivity to an allergen as assessed by oral food challenge) for an allergic reaction to said allergen. The term includes, for example, reducing a food allergic response upon oral exposure to a known allergen (eg, a food allergen) by a minimum of 80% from baseline (eg, 85%, 90% from baseline). The term also includes protection from potentially life-threatening IgE-induced allergic reactions and more particularly IgE-induced anaphylaxis.

As used herein, the term "anaphylaxis" refers to a serious, life-threatening systemic illness characterized by rapid onset with potentially life-threatening airway, respiratory, or circulatory system impairment. As a hypersensitivity reaction, it is defined according to the World Allergy Organization Guidance 2020 and is usually, but not always, accompanied by skin and mucous membrane changes. A wide variety of molecules can induce anaphylaxis. These are the most common proteins that induce anaphylaxis in an IgE-dependent manner or molecules that directly activate mast cells. IgE-mediated anaphylaxis is the interaction of an allergen (usually a protein) with an allergen-specific IgE/high affinity receptor (FcεRI) complex expressed on effector cells, primarily mast cells and basophils. caused by.

As used herein, the phrase "population of subjects" is used to mean a group of subjects.

As used herein, the term "subject" refers to an animal. Typically the animal is a mammal. Subject also refers to, for example, primates (eg, humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In a preferred embodiment, the subject is a human. The term "subject" is used interchangeably with "patient" when it refers to a human.

As used herein, a subject is in "need" of treatment or prophylaxis if the subject would benefit biologically, medically, or in quality of life from the treatment. There is.”

In certain embodiments of the disclosed methods, a BTK inhibitor, such as LOU064 or a pharmaceutically acceptable salt thereof, is used to treat a population of subjects with an IgE-induced food allergic reaction to one or more allergens. be done.

As defined herein, the terms "IgE-induced allergy (or allergic reaction) to one or more allergens" or "IgE-mediated allergy (or allergic reaction)" are used interchangeably, e.g. drug allergy , poison allergy or food allergy (or allergic reaction), preferably refers to an allergic reaction to food allergens such as peanuts, nuts, milk, wheat, soybeans, eggs, sesame, seafood or mixtures thereof. In certain embodiments, food allergy also includes anaphylaxis following accidental exposure to food allergens, e.g., in adult and pediatric patients 2 years of age or older with a confirmed or suspected diagnosis of IgE-induced food allergy to one or more allergens. Refers to indications for the prevention of allergic reactions, including. The term "IgE-induced food allergic reaction" is an adverse reaction to food, caused by an uncontrolled type 2 immune response.

In certain embodiments, drug allergy includes anaphylaxis following exposure to drug allergens, e.g., in adult and pediatric patients over 2 years of age, with a confirmed or suspected diagnosis of IgE-induced allergy to one or more allergens. Refers to indications for the prevention of allergic reactions.

IgE-mediated reactions are usually divided into immediate-onset reactions (occurring up to 2 hours after food ingestion) and immediate-plus-late (immediate-onset symptoms followed by long-term or persistent symptoms). IgE-mediated drug- or food-related reactions include skin symptoms (e.g., angioedema, acute urticaria); gastrointestinal reactions (symptoms include itching and swelling of the lips, tongue, and palate, laryngeal edema, nausea, abdominal cramps, and vomiting) respiratory reactions (which may include, for example, allergic rhinitis and conjunctivitis and bronchoconstriction); systemic reactions (rapidly progressive anaphylaxis, typically combined with gastrointestinal (GI) or respiratory symptoms, and cardiovascular collapse); It is a multi-organ system reaction including

Subjects who are non-responders to treatment with a BTK inhibitor, such as LOU064 or a pharmaceutically acceptable salt thereof, have failed to achieve an improvement of at least 80% of baseline or have had an exacerbation of symptoms. defined as a body. A responder to treatment with LOU064 or a pharmaceutically acceptable salt thereof is defined as a subject who achieves a minimum improvement of 80% over baseline.

The term "oral immunotherapy" or "OIT" is used to treat an allergen to which an allergic patient is allergic (e.g., a food allergen) in order to induce a safer immune response to said allergen and to induce a degree of desensitization. It is a treatment in which increasing doses of phthalate are taken gradually over a period of months. OIT therapy consists of two phases: 1. 2. The titration phase consists of slowly increasing the amount of allergen - this phase can take many months; and 2. maintenance phase, where the patient maintains the same dose; Unfortunately, the titration phase presents a risk of serious allergic reactions, including anaphylaxis. Patients who are able to reach maintenance doses are generally protected from reactions due to accidental exposure as long as they take OIT.

The term "sublingual immunotherapy" or SLIT is another form of allergy immunotherapy that generally involves administering an allergen under the tongue on a daily basis. Currently, the only forms of SLIT approved by the FDA are tablets against ragweed, northern grasses such as green grass, and dust mites. The tablet is placed under the tongue for 1 to 2 minutes and then swallowed as it dissolves. This process is repeated three to every day a week. The tablets increase tolerance to pollen and reduce symptoms over time. For continued effectiveness, treatment may be required for three years or more. Allergy tablets for ragweed and grass pollen only are currently available.

The term "transdermal immunotherapy" or EPIT is another form of allergen immunotherapy that consists in delivering allergens by repeated applications to the skin. EPIT uses a patch and aims to produce persistent sensitization or tolerance through continuous (and constant) allergen exposure to the skin.

As used herein, "select" and "selected" in reference to patients mean that a particular patient is selected from a larger group of patients based on (by) a particular patient having predetermined criteria. used to mean specifically selected from Similarly, "selectively treating" or "selectively preventing" refers to treating patients with a particular disease (e.g., patients known or suspected of having an allergic reaction to a particular food allergen). Refers to providing treatment or prophylaxis in which the patient is specifically selected from a larger group of patients based on the particular patient having predetermined criteria. Similarly, "selectively administering" refers to administering a drug to patients that are specifically selected from a larger group of patients based on (by) a particular patient having predetermined criteria. "Select," "selectively treat," and "selectively administer" mean that a standard treatment regimen is not delivered solely based on the patient's membership in a larger group; patient's medical history (e.g., past therapeutic interventions, e.g., past treatment with biologics), biology (e.g., certain genetic markers), and/or symptoms (e.g., not meeting certain diagnostic criteria) This means that an individualized treatment is delivered to the patient. As used herein, selecting, with respect to methods of treatment, does not refer to the chance treatment of patients with particular criteria, but rather to administering a treatment to a patient based on the patient having particular criteria. refers to the careful selection of Therefore, selective treatment/administration is a standard treatment/administration that delivers a particular drug to all patients with a particular disease, regardless of patient history, disease symptoms, and/or biology. different. In certain embodiments, the patient was selected for treatment based on having a known allergic response to exposure to a food allergen.

The term "pharmaceutical combination" as used herein means the product obtained from the use or mixing or combination of two or more active ingredients. It is to be understood that pharmaceutical combinations as used herein include both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients (e.g., a compound of formula (I) or a pharmaceutically acceptable salt or polymorph thereof) and one or more combination partners are present in a single means to be administered to a patient simultaneously as an entity or dosage form. The term in such cases refers to a combination of fixed doses in one unit dosage form (eg, a capsule, tablet, or sachet). The terms "non-fixed combination" or "kit of parts" both mean that the active ingredients, e.g., a compound of the present disclosure and one or more combination partners and/or one or more auxiliaries , is meant to be administered independently or co-administered to a patient as separate entities, either simultaneously, in parallel or sequentially, without any particular time limit, and such administration specifically includes: If these time intervals allow the combination partners to exhibit a synergistic effect, such as an additive or synergistic effect, they will provide therapeutically effective levels of the two compounds in the patient's body. The term "non-fixed combination" also applies to cocktail therapy, eg the administration of three or more active ingredients. Thus, the term "non-fixed combination" means that the compounds described herein can be administered independently of each other, i.e. at the same time or at different times, in particular in the administration, use, composition. or define the formulation. The term "non-fixed combination" refers to the combination of a single agent, e.g. LOU064 or a pharmaceutically acceptable salt or polymorph thereof, with each independent preparation containing different amounts of the active ingredient therein. It is to be understood that use with fixed combination products of the above is also included. The combination products described herein as well as the term "non-fixed combination" encompass the active ingredients (including the compounds described herein) and the combination partners are sold independently of each other. It should be further understood that the drug may be administered as an entirely separate pharmaceutical dosage form or formulation. Instructions for use of the loose combination may be provided or provided on the packaging, such as a leaflet, or other information provided to the physician and/or medical staff. The independent formulations or parts of the formulation, product or composition may then be administered simultaneously or staggered, i.e. each individual part of the kit of parts may be administered for any part of the kit of parts. They may be administered at different times and/or at equal or different time intervals. In particular, the time interval of administration is such that the effect on the disease treated by the combined use of the parts is greater than the effect obtained by the use of the compound of formula (I) or its pharmaceutically acceptable salt or polymorph alone. / selected to be high; therefore, the compounds used in the pharmaceutical combinations described herein are jointly active. The ratio of the total amount of a compound of formula (I) or a pharmaceutically acceptable salt or polymorph thereof to the second agent administered as a pharmaceutical combination will depend on the needs of the particular patient subpopulation being treated, or, for example, It may be modified or adjusted to better suit the needs of a single patient depending on the patient's age, gender, weight, etc.

As used herein, terms such as "co-administration" or "administration in combination" refer to the administration of one or more compounds described herein together with selected combination partners as required. is meant to encompass administration to a single subject (e.g., a patient or subject) in which the compounds are intended to be administered, and may include treatment regimens in which the compounds are not necessarily administered by the same route of administration and/or at the same time. intended.

The terms "adjuvant" or "adjuvant therapy" or "adjuvant therapy" are treatments given in addition to primary or initial therapy to maximize efficacy and improve safety. In the context of the present invention, adjuvant therapy is the use of a BTK inhibitor (eg LOU064) in addition to the primary therapy of oral immunotherapy (OIT). For example, adjunctive therapy (ie, BTK inhibitor or LOU064) is given before the main treatment (eg, OIT) and during the titration phase of OIT to prevent allergic and/or anaphylactic reactions during the titration phase.

LOU064
LOU064 (=N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2- Fluorobenzamide (INN: remibrutinib) is disclosed in WO 2015/079417 A1 as a drug candidate for selective inhibition of Bruton's tyrosine kinase. This compound is a potent, highly selective, irreversible covalent BTK inhibitor. Due to binding to the inactive conformation of BTK, LOU064 exhibits excellent kinase selectivity, thus reducing kinase off-target binding, and covalent inhibition makes the compound less susceptible to long-term, high systemic compound exposure. (Angst, D. et al., Discovery of LOU064 (Remibrutinib), a Potent and Highly Selective Covalent Inhibitor of Bruton's Tyrosine Kinase, J Med Chem.2020 May 28;63(10):5102-5118).

によって表される遊離塩基である。 LOU064 for use in the methods of the invention has the formula (I):

is the free base represented by

In other embodiments, N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl -2-fluorobenzamide is an anhydrous crystalline form A of the free base, as disclosed in WO 2020/234779 (Example 1), which is incorporated herein by reference.

LOU064, which has already been proposed for use in the treatment of chronic spontaneous urticaria (CSU) (WO 2020/234782 brochure A1) and Sjögren's syndrome (SjS) (WO 2020/234781 brochure A1), SjS (Phase 2); currently being tested in clinical trials for CSU and MS (Phase 3).

In WO 2020/234782 A1, it was generally suggested that twice daily (b.i.d.) administration of doses of 10 mg, 25 mg and 100 mg achieves maximum efficacy in CSU.

In a phase 2b, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of remibrutinib over 12 weeks in patients with at least moderately active CSU who were inadequately controlled with H ₁ -antihistamines. The patient received remibrutinib 10 mg q. d. (once a day), 35 mg q. d. , 100 mg q. d. , 10 mg b. i. d. (twice a day), 25 mg b. i. d. , 100 mg b. i. d. , or placebo (1:1:1:1:1:1:1 ratio). 25 mg b. i. d. The following regimen was found to be particularly effective.

It was reported that BTK occupancy in blood and/or tissues is a suitable biomarker for selecting doses for clinical trials such as CSU and SjS trials (WO 2020/234782 pamphlet and International Publication No. 2020/234781 pamphlet).

Furthermore, it has been reported that the BTK occupancy rate and the duration of the BTK occupancy rate are different in the blood and various tissues of female rats (International Publication No. 2020/234781 pamphlet).

BTK occupancy in different tissues is relevant for efficacy and optimal dose selection in different indications. However, there is currently no consensus picture of all the tissues involved in the multiple allergic reactions caused by food allergy, and thus the tissues that need to be penetrated to treat or prevent IgE-induced food allergic reactions. As reported in rats, BTK occupancy and BTK occupancy half-life differ in blood and various tissues.

Furthermore, BTK occupancy half-life depends on the turnover rate (the ability of the BTK protein within the cell to regenerate). Such turnover rates vary in each tissue and are species-specific. BTK occupancy is further dependent on the PK/PD properties of the compound, which are also species-specific.

Therefore, clinical response on oral food challenge cannot be predicted using the CSU dose or any doses disclosed for other indications.

Pharmaceutical compositions for use in the methods of the invention A BTK inhibitor, i.e. a compound of formula (I), or a pharmaceutically acceptable salt or polymorph thereof, when combined with a pharmaceutically acceptable carrier , can be used as a pharmaceutical composition. Such compositions include, in addition to the compound of formula (I) or a pharmaceutically acceptable salt or polymorph thereof, carriers, various diluents, fillers, salts, buffers, stabilizers, solubilizing agents. , and other materials known in the art. The characteristics of the carrier will depend on the route of administration. Pharmaceutical compositions for use in the disclosed methods may also contain additional therapeutic agents for the treatment of certain targeted disorders. For example, the pharmaceutical composition may also include anti-inflammatory or anti-pruritic agents. Such additional factors and/or agents may be used to produce a synergistic effect with a compound of formula (I) or a pharmaceutically acceptable salt or polymorph thereof, or may be included in pharmaceutical compositions to minimize side effects caused by the salt or polymorph. In preferred embodiments, pharmaceutical compositions for use in the disclosed methods contain the formula (I) or a pharmaceutically acceptable salt or polymorph thereof.

Suitable compositions for oral administration are in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs containing an effective amount of the present invention. Including compounds of the invention. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions, such compositions providing a pharmaceutically sophisticated and palatable formulation. To achieve this, it may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives. Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as corn starch, or alginic acid; binders, such as starch, gelatin or acacia; and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained activity over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use may be prepared as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in a water or oil medium such as peanut oil, liquid paraffin. Alternatively, it may be provided as a soft gelatin capsule mixed with olive oil.

Pharmaceutical compositions for use in the disclosed methods can be manufactured by conventional methods. In one embodiment, the pharmaceutical composition is provided for oral administration. For example, the pharmaceutical composition may be
a) Diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine;
b) Lubricants, such as silica, talcum, stearic acid, its magnesium or calcium salts and/or polyethylene glycol; also for tablets c) Binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, Sodium carboxymethylcellulose and/or polyvinylpyrrolidone; as required d) Disintegrants, such as starch, agar, alginic acid or its sodium salts, or effervescent mixtures; and/or e) Absorbents, colorants, flavors and sweeteners. It is a tablet or gelatin capsule containing the active ingredient along with.

Accordingly, a pharmaceutical composition for use in the methods of the invention comprises LOU064 and one or more pharmaceutically acceptable carriers, each independently a filler, a lubricant, a binder, a disintegrating agent. selected from agents and glidants.

In another embodiment, a suitable pharmaceutical composition, LOU064, may be present in any pharmaceutically acceptable form. Preferably, the pharmaceutical composition will be in tablet or capsule form. Tablets may be film-coated or enteric-coated according to methods known in the art. It may also be preferable to include LOU064 in pharmaceutical compositions/formulations as nano- or micro-sized particles.

When LOU064 is present in the pharmaceutical formulation in the form of nanosized particles, the average particle size may be less than 1000 nm. Preferably, the average particle size of LOU064 may be less than 500 nm, more preferably less than 250 nm.

In preferred embodiments, the average particle size of LOU064 can be about 50 nm to about 1000 nm, or about 50 nm to about 750 nm, or about 60 nm to about 500 nm, or about 70 nm to about 350 nm, or about 100 nm to about 170 nm, and more preferably The average particle size of LOU064 can be from about 100 nm to about 350 nm, or from about 110 nm to about 200 nm, or from about 120 nm to about 180 nm, or from about 120 nm to about 160 nm, preferably, the average particle size of LOU 064 is from about 150 nm to about It can be 200 nm.

When LOU064 is present in a pharmaceutical formulation in the form of nanosized particles, oral administration is preferably at a dose of about 50 mg to about 150 mg twice a day, more preferably at a dose of about 100 mg twice a day. be.

When LOU064 is present in the pharmaceutical formulation in the form of microsized particles, the average particle size may be 1-5 μm or preferably 1.0-1.5 μm. Preferably, the average particle size of LOU064 may be between 1.1 and 1.3 μm.

When LOU064 is present in a pharmaceutical formulation in the form of microsized particles, oral administration is preferably at a dose of about 100 mg to about 300 mg twice a day, such as a dose of about 100 mg twice a day.

In a preferred embodiment, the polydispersity index (PI) is between 0.01 and 0.5, more preferably between 0.1 and 0.2, especially between 0.12 and 0.14. A preferred particle size distribution is shown in FIG.

The above average particle size is weighted by intensity. Average particle size can be determined by dynamic light scattering. Preferably, the average particle size is determined by photon correlation spectroscopy (PCS). In particular, to determine the average particle size, Malvern Panalytical Ltd. The device "Zetasizer Nano ZS" manufactured by (UK), Version 7.13 may be used.

Preferably, the measurement is carried out as a wet dispersion method using a 0.1 mM NaCl solution in purified water (1:10), where the attenuator index is between 2 and 9, in particular 5. The measurements are preferably carried out at 25°C. Further preferred settings of the measurement system are as follows:
Cell: Disposable sizing cuvette Count rate (kcPs): 315
Duration: 60 seconds Measurement position (mm): 4.65.

In one embodiment of the invention, the LOU064 composition is formulated according to routine procedures as a pharmaceutical composition adapted for oral administration to humans. Typically, compositions for oral administration are capsules or tablets.

In one embodiment, the formulation for LOU064 is disclosed in U.S. Provisional Patent Application No. 63/141,558 or a family member thereof (e.g., WO 2022/162,513), which is incorporated herein by reference. The drug is formulated according to the following formulation.

According to the present invention, a suitable pharmaceutical composition for oral administration comprises LOU064 and a binder.

Suitable binders include polyvinylpyrrolidone-vinyl acetate copolymer, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, hypromellose, carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, carboxyethylcellulose, carboxymethylhydroxyethylcellulose, polyethylene glycol, polyvinyl alcohol, shellac, Mention may be made of polyvinyl alcohol-polyethylene glycol copolymers, polyethylene-propylene glycol copolymers, or mixtures thereof. Preferably, the binder is polyvinylpyrrolidone-vinyl acetate copolymer.

The weight ratio of LOU064 and binder can be from about 3:1 to about 1:3; such as about 3:1, about 2:1, about 1:1, preferably the weight ratio of LOU064 and binder is about 2 :1 or about 1:1.

Preferably, a suitable pharmaceutical composition for oral administration comprises LOU064, a binder and a surfactant.

Suitable surfactants include sodium lauryl sulfate, potassium lauryl sulfate, ammonium lauryl sulfate, sodium lauryl ether sulfate, polysorbate, perfluorobutane sulfonate, dioctyl sulfosuccinate, or mixtures thereof. Preferably the surfactant is sodium lauryl sulfate.

The weight ratio of LOU064, binder and surfactant is about 2:1:0.5, or about 2:1:0.1, or about 2:1:0.08, or about 2:1:0.05. , or about 2:1:0.04, or about 2:1:0.03, or about 2:1:0.02. Preferably, the weight ratio of LOU064, binder and surfactant is about 2:1:0.08 or about 1:1:0.05.

In a particularly preferred embodiment, a suitable pharmaceutical composition for oral administration comprises LOU064, a binder and a surfactant, where the binder is polyvinylpyrrolidone-vinyl acetate copolymer (copovidone) and the surfactant is Sodium lauryl sulfate (SLS), and the weight ratio of LOU064, copovidone and SLS is about 2:1:0.08. It is even more particularly preferred that LOU064 is present in the pharmaceutical composition in the form of nanosized particles, preferably having an average particle size of about 100 nm to about 200 nm as measured by PCS.

A method of treatment or prevention using LOU064 or a pharmaceutically acceptable salt thereof or a crystalline form thereof.
Methods and BTK inhibition for use in preventing, treating or modifying the course of IgE-induced allergic reactions to one or more allergens, such as poisons, drugs or foods, such as peanuts, in a subject in need thereof. Agents, e.g., irreversible BTK inhibitors, e.g., compounds of formula (I) (i.e., LOU064) or pharmaceutically acceptable salts or polymorphs thereof, are disclosed herein and are disclosed herein for therapeutically effective doses of comprising administering LOU064 or a pharmaceutically acceptable salt thereof to a subject. In one aspect of this embodiment, the invention provides LOU064 or a pharmaceutically acceptable derivative thereof for use in preventing an IgE-induced food allergic reaction to one or more allergens, such as peanuts, in a subject in need thereof. comprising administering to a subject a therapeutically effective dose of LOU064 or a pharmaceutically acceptable salt thereof. LOU064 for use in the disclosed methods can be incorporated into pharmaceutical compositions and administered in vivo to treat poison, drug or food allergic patients (i.e., human patients), as described above.

For example, an IgE-induced food allergic reaction to one or more allergens is a food allergic reaction, such as a peanut allergic reaction.

In yet another example, the IgE-induced food allergic reaction disease or disorder to one or more allergens refers to peanut, nut, milk, wheat, soybean, egg, sesame, seafood allergic reactions.

In another embodiment, the subject suffers from a food allergy, such as a peanut allergy.

The ability of LOU064 to inhibit defined allergen responses was evaluated by skin prick test (SPT) in healthy atopic subjects in the multiple dose escalation (MAD) study part of a first-in-human study. SPT with seven allergens (grass pollen mixture, birch tree pollen, alder tree pollen, hazel tree pollen, dust mite, cat dander and horse dander) before any administration (baseline) and after 1 and at different time points after 11 days of once-daily administration. The study demonstrated a dose-dependent reduction in wheal size up to a dose of 100 mg. Above 100 mg, no dose-dependent trend was evident, but the highest reduction was observed at the highest tested dose (600 mg q.d.). Across all studies, participants received 100 mg qd. The above doses showed an average reduction in wheal size of 3 mm (Kaul et al. Clin. Transl. Sci. 2021; 14(5), pp 1756-1768).

Dose-dependent inhibition of FcεR1-mediated basophil activation was also demonstrated with LOU064 during first-in-human studies. In a single dose ascending study (SAD) of LOU064, ex vivo blood basophil activation, as measured by CD63, was almost completely inhibited (>89%) at the 60 mg dose and at the higher dose 24 hours after dosing. Almost 100% inhibition was reached. Doses of 100 mg and above demonstrated nearly complete inhibition. In contrast, another basophil activation marker, CD203c+, showed up to 79.4% inhibition at 8 hours in the 200 mg cohort. In a repeated dose-escalation study (MAD), complete inhibition of blood basophil activation, as measured by CD63 expression, was observed for the entire treatment period (days 1-12) and at daily doses of 50 mg or more of LOU064. This was achieved over several days. Trough level inhibition of CD63 on the last day of administration was 10 mg. q. d. 80% at the lowest tested dose (once daily); this was more potent at either higher dose. Dose-dependent inhibition was observed for the CD63 marker, with 100 mg q. d. Thus, more than 97% trough inhibition was achieved. Inhibition of CD203c+ basophils was 63% and 67%, respectively, at 400 mg q. d. and 200mg b. i. d (Kaul et al. Clin. Transl. Sci. 2021; 14(5), pp 1756-1768).

Furthermore, the present inventors demonstrated that in an ovalbumin-induced anaphylaxis mouse model (Example 3), treatment with LOU064 (10 mg/kg, 30 mg/Kg) demonstrated a significant reduction in the number of macrophages, macrophages, and lymphocytes). Based on those results and a translation model between animals and humans (Journal of basic and clinical pharmacy, 7(2), 27-31), the calculated human equivalent dose (HED) for 30 mg/kg was: Equivalent to approximately 170 mg for a 70 kg person, the calculated human equivalent dose (HED) for the lowest effective dose of 10 mg/kg is equivalent to approximately 56 mg for a 70 kg person (Nair, A.B., & Jacob , S. (2016).

Finally, according to an in-house predictive model for splenic BTK occupancy in humans (Example 7), twice-daily (b.i.d.) dosing may result in higher BTK occupancy at the same dose. was shown to be more effective than QD administration (Figure 13). Therefore, 25mg b. i. The dose of LOU064 in d is the lowest human effective dose, 100 mg b. i. d. Doses of 0.25% are also shown to be effective in humans.

The appropriate dosage depends, for example, on the particular pharmaceutically acceptable salt of LOU064, the particular polymorphic form of LOU064, the host, the method of administration, the pharmaceutical composition, and the nature and severity of the condition being treated, and the subject. It will vary depending on the nature of previous treatments the body has received.

In a preferred embodiment, LOU064 may be administered regardless of body weight, gender, age, or race. For example, a 35 year old woman weighing 60 kg is preferably administered the same dose as a 50 year old man weighing 90 kg. Notably, body weight, sex, age or race have no clinically significant effect on the pharmacokinetics of LOU064.

Ultimately, the responsible health care professional will determine the amount of LOU064 to treat each individual subject. In certain embodiments, the attending health care professional may administer a low dose of LOU064 and observe the subject's response.

In one embodiment of the present disclosure, LOU064 or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 20 mg to about 200 mg daily.

In another embodiment, LOU064 or a pharmaceutically acceptable salt thereof is administered at a dose of about 25 mg daily, or about 50 mg daily, or about 75 mg daily, or about 100 mg daily. In one aspect of this embodiment, LOU064 is administered at a dose of about 25 mg QD (once daily), or about 50 mg QD, or about 75 mg QD, or about 100 mg QD.

In one embodiment of the present disclosure, LOU064 or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 mg twice a day to about 100 mg twice a day, such as about 10 mg twice a day (B.I.D.). , about 25 mg B. I. D. Approximately 50 mg B. I. D or about 100mg B. I. It is administered orally at a dose of D.

In another embodiment, LOU064 is administered orally at a dose of about 10 mg twice daily.

In another embodiment, LOU064 is administered orally at a dose of about 25 mg twice daily.

In another embodiment, LOU064 is administered orally at a dose of about 50 mg twice daily.

In another embodiment, LOU064 is administered orally at a dose of about 75 mg twice daily.

In another embodiment, LOU064 is administered orally at a dose of about 100 mg twice daily.

The duration of treatment using the pharmaceutical compositions of the present disclosure will vary depending on the severity of the disease or disorder being treated and the medical condition and personal response of each individual subject. In certain embodiments, the subject is administered LOU064 for a short period of time, such as up to 4 weeks, such as up to 6 weeks, such as up to 8 weeks, such as up to 10 weeks, such as up to 12 weeks. LOU064 is defined herein above, for example, to prevent severe food allergic reactions and trigger avoidance during business trips and/or vacations, and any other situations where exposure to allergens is not adequately controlled. For example, it can be administered over a short period of time.

In certain embodiments, LOU064 is administered at least 2 days prior to the potential risk of exposure to an allergen (eg, a food allergen). In another embodiment, LOU064 is administered within at least 1 week, such as 1 week, 2 weeks, 3 weeks, or 4 weeks before the potential risk of exposure to an allergen (e.g., a food allergen). . The advantage of LOU064 over anti-IgE therapy is its fast onset of action to achieve maximum protection/prevention of allergic reactions.

In certain other embodiments, the subject is administered LOU064 for an extended period of time (e.g., LOU064 is administered for as long as the disease exists to justify its use, e.g., at least 6 months, e.g., at least 10 months, LOU064 or a pharmaceutically acceptable salt thereof may be used indefinitely for a total period of over 1 year, e.g. 1 year, 2 years, 3 years, 4 years, 10 years. It may be used for years, 10 years, 15 years, 20 years, or for life. In certain embodiments, treatment with LOU064 is chronic treatment.

In practicing some of the methods of treatment or use of this disclosure, a therapeutically effective dose of LOU064, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., a mammal (e.g., a human). Ru. While it is understood that the disclosed methods provide for the treatment or prevention of IgE-induced food allergic reactions using LOU064 or a salt thereof, this does not necessarily mean that the treatment is a monotherapy.

In one aspect of the invention, a BTK inhibitor, eg, an irreversible BTK inhibitor, eg, LOU064, is administered to a subject as a monotherapy.

In another aspect of the invention, a BTK inhibitor, eg, an irreversible BTK inhibitor, eg, LOU064, is administered to a subject as a combination therapy.

Indeed, if a subject is selected for treatment with LOU064, LOU064 may be used in combination with other agents and therapies to treat a subject suffering from an IgE-related disease or disorder, e.g. In combination with one additional therapeutic agent, such as an anti-IgE antibody (eg, omalizumab or ligelizumab), a corticosteroid or an immunosuppressant, such as a systemic corticosteroid or an immunosuppressant, may be administered according to the methods of the present disclosure.

In certain embodiments of the disclosed uses, methods, and kits, the subject has an IgE-induced allergic response to one or more allergens, where the allergen is a drug or a food, e.g., a food, e.g., peanuts. . In certain embodiments, the subject may also have asthma and/or urticaria, eg, a disease or disorder selected from asthma, allergic asthma, rhinitis, allergic rhinitis, urticaria, and CSU. In certain embodiments of the disclosed uses, methods, and kits, the subject is allergic to one or more allergens (e.g., foods such as peanuts, nuts, milk, wheat, soy, eggs, sesame, seafood, or mixtures thereof). have an IgE-induced food allergic reaction to allergens).

In other embodiments of the disclosed uses, methods, and kits, the subject has an IgE-induced food allergic response to one or more allergens, where the allergen is a food, such as peanuts.

For example, if the subject to be treated is allergic, or the subject also has another disease selected from asthma, urticaria, and rhinitis, such as allergic asthma, CSU, and allergic rhinitis; This may apply if you are suffering from a disability.

When co-administered with one or more additional agents, LOU064 or a pharmaceutically acceptable agent thereof may be administered simultaneously or sequentially with the other agents. If administered sequentially, the attending physician will determine the appropriate order of administration of LOU064 or a pharmaceutically acceptable salt thereof in combination with other agents and the appropriate dosage for co-delivery. .

Various therapeutic modalities may be beneficially combined with the disclosed LOU064 in the treatment of IgE-related diseases or disorders disclosed herein. Such treatments include, for example, anti-IgE antibodies (e.g. omalizumab, ligelizumab), corticosteroids (e.g. inhaled or systemic corticosteroids), immunosuppressants, leukotriene receptor antagonists (LTRA), short-acting Included are beta agonists (SABA) or long-acting beta agonists (LABA).

In certain embodiments of the disclosed uses, methods, and kits, LOU064 or a pharmaceutically acceptable salt thereof may be prescribed as a first-line treatment or added to any of the standard treatments.

In another embodiment, LOU064 or a pharmaceutically acceptable salt may be administered according to the methods of the present disclosure in combination with other agents and treatments for treating IgE-induced food allergic reactions.

In one embodiment, LOU064 or a pharmaceutically acceptable salt thereof is administered in conjunction with oral immunotherapy (OIT), sublingual immunotherapy (SLIT), transdermal immunotherapy (EPIT), preferably in conjunction with OIT. . In one aspect of this embodiment, LOU064 is administered as an adjunctive therapy to OIT.

Oral immunotherapy (OIT) is a potential treatment for food allergies that involves increasing amounts of food allergens given under medical supervision. Such a procedure results in desensitization to the allergen. OIT treatments are costly and labor intensive as they typically require hospitalization of the patient due to the risk of potentially life-threatening reactions.

In one embodiment, a BTK inhibitor, e.g. an irreversible BTK inhibitor, e.g. Reduce the frequency and severity of systemic reactions (e.g. allergic reactions such as anaphylaxis).

In another embodiment, a BTK inhibitor, e.g. an irreversible BTK inhibitor, e.g. of patients successfully complete OIT.

In one embodiment, a BTK inhibitor, eg, an irreversible BTK inhibitor, eg, LOU064, is administered as an adjunct therapy to OIT treatment with peanut protein.

To date, the single currently approved OIT product for alleviating allergic reactions in peanut allergic patients is Palforzia™. Thus, a BTK inhibitor, eg, an irreversible BTK inhibitor, eg, LOU064 t, can be administered according to the methods of the present disclosure as an adjunct to peanut protein (eg, Palforzia™).

In one embodiment, a BTK inhibitor, e.g. an irreversible BTK inhibitor, e.g. ) or starting at least 2 weeks (14 days) before. In one aspect of this embodiment, the BTK inhibitor, e.g., an irreversible BTK inhibitor, preferably LOU064, for use according to the methods described herein is further and then discontinue LOU064 at the beginning of the maintenance phase of OIT.

Patient Selection In one embodiment, the patient is an adult (18 years of age or older).

In another embodiment, the patient is an adolescent (12-17 years old).

In yet another embodiment, the patient is a pediatric patient (2-11 years old or 6-11 years old).

In another embodiment of the invention, the patient to be administered a BTK inhibitor, e.g. an irreversible BTK inhibitor, e.g. LOU064, for the treatment or prevention of an IgE-induced food allergic reaction is selected according to the following criteria:
a) Male and female patients, aged 2 years or older (eg 2-5 years or 6-11 years, 12-17 years or 18-55 years);
b) Confirmed history of allergies to foods including but not limited to peanuts, nuts, wheat, eggs, milk, soy, seafood;
c) positive allergen-specific IgE (e.g. peanut sIgE ≧6 kUA/L at screening);
d) A positive skin prick test for an allergen to which the patient is allergic (e.g. defined as a wheal with a mean diameter (longest diameter and midpoint orthogonal diameter) ≧4 mm compared to a negative control).

In one aspect of the above embodiments, the patient receiving LOU064 or a pharmaceutically acceptable salt thereof does not have uncontrolled asthma, defined as having one of the following criteria:
- Patient's predicted normal FEV1 <80% at the time of the first screening visit
- One hospitalization for asthma within the 12 months prior to the screening visit.

Efficacy In one embodiment, the present invention relates to a BTK inhibitor, e.g. an irreversible BTK inhibitor, e.g. A targeted BTK inhibitor, such as LOU064, achieves prophylaxis at x weeks of treatment. In one aspect of this embodiment, prevention is defined as a minimum 80% reduction from baseline (eg, a minimum 85% reduction or a minimum 90% reduction from baseline).

In one embodiment, the present invention relates to a BTK inhibitor, e.g. an irreversible BTK inhibitor, e.g. LOU064, for use in the methods described herein, wherein at least one of the following is true: :
up to 4 weeks (e.g. 1 week, or 2 weeks, or 3 weeks or 4 weeks) after treatment with LOU064;
- at least 90% of the treated patients do not show an allergic reaction upon a food challenge of 600 mg of food allergen (eg 600 mg of peanut protein);
- at least 90% of treated patients show no allergic reaction upon food challenge of 1000 mg of food allergen (eg 1000 mg of peanut protein);
- At least 80% of the treated patients do not show an allergic reaction upon a food challenge of 3000 mg of food allergen (for example 3000 mg of peanut protein).

In another embodiment, the invention relates to LOU064 for use in the methods described herein, wherein the patient achieves a reduction from baseline in a total domain score FAQLQ of 0.45 to 0.5. .

FALQLQ (Food Allergy Quality of Life Questionnaire) is a disease-specific health-related quality of life (HRQoL) questionnaire for patients with food allergies. They include the Adult Questionnaire (AF), Child Questionnaire (CF), and Teenager Questionnaire (TF), as well as two questionnaires completed by parents of children with food allergies (Parent Questionnaire PF and Parent Questionnaire PF). Paper Teenager PFT) has been developed and accepted. These questionnaires are reliable and valid tools for measuring the impact of food allergies on HRQoL (health-related quality of life). More specifically, the Food Allergy Quality of Life Questionnaire (FAQLQ) assesses the impact of food allergy on participants' HRQoL (i.e., the domains include risk of accidental exposure, affective effects, allergen avoidance and dietary (consisting of restrictions). FAQLQ-Pediatric Questionnaire (8-12 years old) (Flokstra-de Blok BM et al (2009) Clinical. Exp. Allergy; 39: (1) 127-37), FAQLQ-Teenager Questionnaire (13-17 years old) ( Flokstra-de Block BM et al. (2008) J. Allergy Clinical Immunology; 122:139-44, 144.e1-2) and FAQLQ-Adult Questionnaire (≧18 years) (Flokstra-de Block BM e tal (2009 ) Allergy; 64(8):1209-17) is a self-administered, validated food allergy-specific HRQoL questionnaire. The FAQLQ-Parent Questionnaire (FAQLQ-PF) is completed by parents of children 0 to 12 years of age with food allergies (Dunn Galvin et al (2008), Clin Exp Allergy, 40 (2010), 476- 485).

The number of items and domains will vary depending on the FAQLQ document being implemented. Each question is scored on a 7-point scale from 1 to 7 (ie, "none" to "maximum" reduction in HRQoL, respectively). The total score is the arithmetic mean of all nonmissing items. Domain scores are similarly calculated.

In yet another embodiment, the invention relates to LOU064 for use in the methods of the invention, wherein the patient achieves a reduction from baseline in total domain score FAIM.

The FAIM (Food Allergy Independent Measurement) is a valid and reliable instrument for measuring patient outcome prediction and has been tested in children (FAIM-CF), adolescents (FAIM TF) and adults (FAIM AF). (Flokstra-de Block et al. Allergy 65(5):630-5). The Food Allergy Independent Measure (FAIM) reflects a participant's perceived food allergy severity and food allergy-related risk. The FAIM includes four questions similarly scored from 0 to 6, with higher scores indicating a worse prediction of adverse outcome (eg, severe reaction or death) if the allergen is introduced incidentally.

In yet another embodiment, the invention provides that the observed difference in response rate between treated and untreated patients at a double-blind, placebo-controlled food challenge of 600 mg of allergen (e.g., peanut allergen) is greater than 35%. LOU064 for use in the methods described herein, where the response rate is defined as less than or equal to a mild response to a 600 mg oral food challenge.

In a further embodiment, the invention provides that the patient has no or less than a mild response to an oral food challenge (e.g., after receiving a dose of 600 mg of allergen (e.g., peanut protein)). Relating to LOU064 for use in the methods described herein. Mild responses are recognized by the Consortium of Food Allergy Research (CoFAR: Sampson HA et al. J. Allergy Clin. Immunol; 130), including one or more of the following: (6):1260-74):
- In the skin - limited (slight) or localized hives, swelling (e.g. mild lip edema), skin flushing (e.g. some areas of mild erythema) or mild pruritus (e.g. occasional scratch)
Respiratory - Rhinorrhea (e.g., occasional sniffling or sneezing), nasal congestion, occasional cough, sore throat. GI - Mild abdominal discomfort (mild nausea with or without decreased activity). sporadic vomiting that is thought to be secondary to choking (gag).

In another embodiment, the present invention provides that after a patient has been administered a dose of 600 mg of an allergen (e.g., peanut protein) that does not produce a moderate or severe reaction to an oral food challenge, Relating to LOU064 for use in the methods described.Moderate reactions are recognized by the Consortium of Food Allergy Research (CoFAR: Sampson HA et al. J. Allergy Clin. Immunol; 130 (6), including one or more of the following: ): 1260-74):
Skin - generalized hives (e.g., numerous or widespread hives), swelling (e.g., marked lip or facial edema), pruritus causing persistent scratching, more than a few areas of erythema or marked erythema.Respiratory Organs - Throat tightness without hoarseness, persistent cough, wheezing without difficulty breathing. GI - Persistent moderate abdominal pain/cramps/nausea, vomiting with decreased activity.

Severe reactions are defined according to the Consortium of Food Allergy Research (CoFAR: Sampson HA et al. J. Allergy Clin. Immunol; 130(6):1260-74) including one or more of the following:
・Skin - Severe generalized urticaria/angioedema/erythema ・Respiratory system - Laryngeal edema, throat tightness with hoarseness, wheezing with dyspnea, stridor
・GI – severe abdominal pain/convulsions/recurrent vomiting ・Nervous system – altered mental status ・Circulatory system – clinically significant drop in blood pressure

Safety Up to 600 mg in a single dose and an additional 100 mg over up to 18 days b. i. d. The short-term safety of LOU064 was demonstrated in a Phase I clinical trial. However, no data related to long-term safety are currently available.

Given the dose-limiting side effects observed with the covalent irreversible BTK inhibitors evobrutinib and trebrutinib, evobrutinib was administered at 75 mg b. i. d. Trebrutinib already showed dose-limiting liver enzyme elevations at a dose of Engl J Med; 380(25):2406-17, Smith P.F. et al., 2019, ACTRIMS Forum, Feb 28, 2019, P072), a significant increase in the occurrence of these adverse events was observed even at high doses. The fact that it was not seen in LOU064 is promising. We tested 100 mg b. over an extended period of time (up to 52 weeks). i. d. LOU064 was demonstrated to be safe even at high doses of (Example 14). In particular, LOU064 was administered at 100 mg b. over an extended period of time (up to 52 weeks). i. d. does not induce any dose-limiting liver enzyme elevations and other off-target effects. Therefore, LOU064 is suitable for long-term treatment.

Therefore, one object of the present invention is LOU064 for use in the method described, wherein up to 12 weeks, up to 24 weeks or up to 52 weeks of treatment, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lipase levels do not change by more than 10% compared to baseline levels at the start of treatment.

Therefore, LOU064 not only efficiently prevents IgE-induced allergic reactions (e.g. food allergic reactions), but also significantly improves the effectiveness of acalabrutinib compared to other BTK inhibitors, especially when treatment is maintained over a long period of time. It was particularly surprising that it also had a better safety profile compared to For example, the BTK inhibitors currently approved primarily for the treatment of hematologic malignancies (ibrutinib, acalabrutinib, and zanubrutinib) have known safety hazards. Major safety barriers include infection, effects on platelet function (risk of bleeding), and cytopenias. Other safety concerns for one or more of the approved BTKis include cardiac arrhythmias (atrial fibrillation and flutter) and, for ibrutinib alone, heart failure and hypertension.

Therefore, in a preferred embodiment of the invention, LOU064 or a pharmaceutically acceptable salt thereof for use in treating or preventing IgE-induced allergic reactions (e.g. food allergic reactions) is used for long-term treatment. . The term long-term treatment indicates that LOU064 or a pharmaceutically acceptable salt thereof is used for an extended period of time. For example, LOU064 or a pharmaceutically acceptable salt thereof can be safely used for 6 months, 10 months, 1 year, 2 years, 3 years, 4 years, more than 10 years. LOU064 or a pharmaceutically acceptable salt thereof may be used for up to 2 years, 5 years, 10 years, 15 years, 20 years or for life.

In one embodiment, LOU064 not only efficiently prevents IgE-induced allergic reactions (e.g., food allergic reactions), but also has the following characteristics:
- no clinically relevant increase in the risk of infection;
- no clinically relevant increase in massive bleeding;
- have a safety profile that includes one or more of the following: no clinically relevant elevations of liver enzymes; allowing such long-term treatment;

It is expected that LOU064 oral drug exposure may be increased several-fold when administered with a CYP3A inhibitor, particularly a strong CYP3A inhibitor, such as a strong CYP3A4 inhibitor. Similarly, strong inducers of CYP4A, such as CYP3A4, can significantly reduce exposure and result in decreased efficacy of LOU064. These properties of LOU064 are relevant not only for the treatment and/or prevention of IgE-induced allergic reactions, but also for the treatment and/or prevention of any BTK-mediated pathologies. Potent CYP3A inhibitors or inducers are defined according to FDA 2020 guidelines. Therefore, a potent CYP3A inhibitor (e.g., a CYP3A4 inhibitor) may increase the area under the curve (AUC) by more than 5-fold or increase the clearance by more than 80% after co-administration with LOU064 compared to administration of LOU064 alone. It is an inhibitor that causes a decrease. A strong CYP3A inducer (e.g., a strong CYP3A4 inducer) will increase the AUC by more than 80% (e.g., by 85%, by 90%, by 95%) after co-administration with LOU064 compared to administration of LOU064 alone. ) is an inducer that reduces

Co-administration with strong CYP3A inhibitors and/or inducers, such as strong CYP3A4 inhibitors and/or inducers, may likely cause large changes in LOU064 drug exposure and should be avoided. Potent CYP3A4 inhibitors include boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir/ritonavir, darunavir/ritonavir, elvitegravir/ritonavir, idelalisib, indinavir, indinavir/ritonavir, itraconazole, ketoconazole, LCL161, lopinavir/ritonavir, mibefradil , nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, saquinavir/ritonavir, telaprevir, telithromycin, tipranavir/ritonavir, troleandomycin, Viekira pack or/and voriconazole. CYP3A4 inhibitors may also be included in grapefruit juice.

Therefore, in another preferred embodiment, LOU064 is not administered concurrently with a potent inhibitor and/or inducer of CYP3A4, eg, as defined herein above.

It has further been found that LOU064 can be co-administered with oral contraceptives such as ethinyl estradiol or levonorgestrel without significant effect on their exposure and efficacy. Therefore, in a preferred embodiment, LOU064 is co-administered with an oral contraceptive.

In a preferred embodiment, no premedication is administered before the first administration of LOU064.

As a covalent irreversible BTK inhibitor, LOU064 acts by irreversible inhibition of BTK that is offset by de novo protein synthesis. Thus, without wishing to be bound by any theory, reconstitution of the B cell pool after B cell depletion can take several months, whereas recovery of B cell function after BTK inhibition occurs immediately after withdrawal. In particular, it is believed that this can be achieved within a few days. Therefore, if necessary, the therapy can be stopped quickly, thereby giving clinicians and patients an easier and faster ability to react when unexpected situations arise.

In another embodiment, LOU064 is advantageously selected if the patient is scheduled to undergo chemotherapy within the next 12 months.

Especially in light of the COVID-19 pandemic, B cell depleted patients have a higher risk of infection. Furthermore, the absence of a fully functional adaptive immune response is likely to lead to a more severe course.

However, since LOU064 does not result in depletion of the B cell pool, cessation of treatment leads to rapid recovery of full B cell function. This gives the patient and the treating physician the possibility to respond quickly to infection or vaccination requirements, in particular vaccination with live and attenuated vaccines.

According to the invention, LOU064 may be administered during an infection, such as during a COVID-19 infection. Accordingly, LOU064 administration may be continued during an infection, such as during a COVID-19 infection.

Preferably, LOU064 administration is delayed in patients with an active infection, eg, COVID-19, until the infection has resolved.

Accordingly, one embodiment of the present invention relates to LOU064 for use in the treatment or prevention of IgE-induced allergic reactions (e.g. food allergic reactions) in which patients acutely infected or previously infected with COVID-19 are treated. .

In further embodiments, LOU064 treatment is continued during the COVID-19 infection.

In a preferred embodiment, LOU064 treatment is discontinued during COVID-19 infection and continued after the infection has been overcome.

Yet other embodiments of the invention relate to LOU064 for use in the treatment or prevention of IgE-induced allergic reactions (eg, food allergic reactions), where the patient is vaccinated during LOU064 treatment. Alternatively, patients can be vaccinated during LOU064 treatment with a non-live vaccine. In one embodiment, the patient is vaccinated with a quadrivalent influenza vaccine, PPV-23 vaccine, or KLH neoantigen vaccine during LOU064 treatment (eg, 15 days after starting LOU064 treatment). In one aspect of this embodiment, the patient receiving the quadrivalent influenza vaccine is defined by a >4-fold increase in anti-hemagglutinin antibody titer at 28 days post-vaccination compared to baseline. Achieve a similar response. In another aspect of this embodiment, the patient receiving the PPV-23 vaccine achieves a >2-fold increase in IgG titer 28 days after vaccination compared to baseline. In yet another embodiment, the patient receiving the KLH neoantigen vaccine achieves a T cell-dependent antibody response as measured by anti-KLH IgG and IgM titers 28 days after vaccination.

Another embodiment of the invention provides that LOU064 treatment is discontinued due to vaccination, in particular LOU064 treatment is discontinued 5 to 10 days, such as 7 or 8 days, preferably 6 weeks before vaccination. , treatment of IgE-induced allergic reactions (e.g. food allergic reactions) or continued after vaccination, e.g. 5-20 days, preferably 5-10 days, or most preferably 10-15 days after vaccination. Concerning LOU064 for prophylactic use. In an alternative embodiment, the vaccination is with a live and/or attenuated vaccine. In certain aspects of this embodiment, the patient receives a quadrivalent influenza vaccine, a PPV-23 vaccine, or a KLH neoantigen vaccine after discontinuing LOU064 treatment (e.g., 5-10 days or 7 or 8 days after discontinuing LOU064 treatment). be inoculated with. In one aspect of this embodiment, patients receiving a quadrivalent influenza vaccine are defined by a >4-fold increase in anti-hemagglutinin antibody titers at 28 days post-vaccination compared to baseline. Achieve a similar response. In another aspect of this embodiment, the patient receiving the PPV-23 vaccine achieves a >2-fold increase in IgG titer 28 days after vaccination compared to baseline. In yet another embodiment, the patient receiving the KLH neoantigen vaccine achieves a T cell-dependent antibody response as measured by anti-KLH IgG and IgM titers 28 days after vaccination. LOU064 treatment is then continued starting 29 days after vaccination.

General The details of one or more embodiments of the disclosure are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, the preferred methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the specification and claims. In this specification and the appended claims, the singular forms singular include plural referents (eg, a reaction may include several reactions) unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited herein are incorporated by reference. The following examples are presented to more fully illustrate preferred embodiments of the disclosure.

These examples should in no way be construed as limiting the scope of the disclosed subject matter, which is defined by the appended claims.

Example 1: Passive cutaneous anaphylaxis (PCA) in mice
LOU064 was tested in a mouse PCA model. BALB/c mice aged 8 to 10 weeks were used as the model. For passive sensitization with hapten-specific IgE, mice under isoflurane anesthesia were given an intradermal injection of 20 μl of anti-DNP IgE in saline in the right ear and 20 μl of saline in the left ear. For FcεR-specific PCA, mice received a low dose of 3 ng anti-DNP IgE. For maximum PCA, mice were given a high dose of 25 ng anti-DNP IgE.

LOU064 was administered orally (po) in a volume of 5 ml/kg body weight. The first dose was administered in the evening before challenge, 4 hours after sensitization. The next morning, 2 hours before hapten challenge, mice were given a second oral dose of LOU064. Mice were challenged with hapten 2 hours after the second dose by placing the mice in a heated chamber. The animals were then injected intravenously (i.v.) with 100 μg of hapten DNP-HSA (dinitrophenyl-human serum albumin) in 200 μl of 2% Evans blue diluted in PBS. The mice were then returned to their cages for exactly 30 minutes. After 30 minutes, animals were then anesthetized with isoflurane and bled retroorbitally using EDTA-coated blood collection tubes for analysis of compound exposure. Mice were then sacrificed by cervical dislocation. 6 mm punch biopsies were taken from both left and right ears and placed in 100 μl formalin. Skin biopsies were incubated overnight at 80°C to extract the pigment. After 24 hours, 80 μl of formalin solution was transferred to a clear flat bottom 96-well plate and light absorption was read at 620 nm. Analysis was performed by subtracting the left ear (saline) from the right ear (IgE) to determine how much dye was released into the biopsied skin tissue. Statistical significance was determined by ANOVA. Spleens were removed for BTK occupancy analysis.

Analysis of blood concentrations: Blood samples were taken as indicated and compound measurements were performed. A structurally similar internal standard mixed with acetonitrile (4 volumes) was added to the blood sample and centrifuged at approximately 4000 rpm (4°C). The supernatant was then transferred to a microtiter plate. An aliquot of each sample was injected into the LC-MS/MS system for determination of the concentration of the parent molecule.

The concentration of LOU064 present in mouse blood 2.5 hours after second compound administration is shown for low dose IgE sensitization in Table 1.

Analysis of BTK occupancy in the spleen (Figure 2)
The level of BTK occupancy after administration of LOU064 was determined in separate ELISAs for total BTK protein and bound BTK (=free BTK). Covalent binding of compounds to BTK was determined using an immunoassay for free BTK (ie, not covalently occupied by compound) and total BTK protein. For free BTK measurements, samples were incubated with a biotinylated covalently bound BTK probe (Pulz R et al, ACS Med. Chem. Lett. 2019, 10, 1467-1472), and then samples were subjected to streptavidin ELISA. In addition to the plate, allowed the binding of probe-bound BTK. Probe binding to BTK is mutually exclusive with compound binding to BTK. Plate-bound BTK was detected using anti-BTK antibody (D3H5, Cell Signaling Technology). For total BTK measurements, ELISA plates were coated with D3H5 anti-BTK to capture total BTK. The captured BTK was then detected using anti-BTK antibodies (no. 53, BD Biosciences) directed against different epitopes. Respective free BTK levels for each sample were normalized to total BTK levels in the same sample, and these ratios were expressed as a percentage of the vehicle control sample.

For splenic BTK occupancy, each spleen was triturated and incubated on ice for 10 min in 0.4 ml cold Pierce IP lysis buffer containing protease inhibitor mixture (Complete, Roche #11 836 170 001) and 5 mM EDTA. (Thermo Scientific #87787) in GentleMACS (Miltenyi, #130-093-236) tubes. Spleen lysates were removed by centrifugation and aliquots were incubated with 10 μM covalently biotinylated BTK probe for 2 hours at room temperature. Two separate ELISA assays were performed to determine the relative levels of total BTK protein and BTK-bound covalent probe (corresponding to free unoccupied BTK).

Relative BTK occupancy was calculated as the ratio of free BTK (signal of bound BTK) to total BTK for each sample: Ri = free BTK/total BTK. Individual Ri values were then normalized to the vehicle group and expressed as percent occupancy: (mean Ri vehicle group - Ri)/(mean Ri vehicle group) ^* 100%.

Figure 2 shows relative BTK occupancy in the spleen 2.5 hours after the second oral administration of LOU064. High and near maximal levels of BTK occupancy were seen for all dose levels. Occupancy levels relative to vehicle control were 89.1%±1.7 for 3 mg/kg and 98.4-99.7% for doses of 10-100 mg/kg.

Conclusion:
Based on the above results, the BTK inhibitor, LOU064, is effective in inhibiting FcεR responses in cutaneous mast cells (Figure 1). This study showed that almost complete inhibition of anaphylactic reactions was observed at doses as low as 3 mg/kg. Blood concentrations of LOU064 2.5 hours after the second oral administration showed a dose-proportional increase. Blood exposure in both experiments was comparable. Splenic BTK occupancy measured at the same time point showed proportionally near complete target occupancy for lower doses. In conclusion, LOU064 was demonstrated to significantly inhibit cutaneous anaphylaxis in the murine PCA model after two oral administrations.

Example 2: Reverse Passive Arthus (RPA) Response in Mouse Skin The effect of a single dose of LOU064 was tested in an acute murine Reverse Passive Arthus (RPA) model to induce FcGRIII on mast cells triggered by IgG immune complexes. evaluated its effect on cutaneous anaphylactic reactions mediated by. Female C57Bl6 mice (Charles River, France), 8-10 weeks old, were used. The backs of mice were shaved 24 hours before skin injection. This made it possible to eliminate any potential irritation of the skin. Arthus reactions were elicited after 2 hours of compound in dose-response studies or at the time points indicated in time-course studies. To elicit the Arthus reaction, 50 μl of PBS (control site) or polyclonal rabbit anti-ovalbumin IgG at a concentration of 30 μg in PBS (C6534, Sigma) was injected intradermally (i.d.) in the dorsal skin. Immediately after the intradermal injection, an intravenous (i.v.) injection of 200 μl of ovalbumin (20 mg/kg) in saline (05450 Fluka) was performed. Three hours after ovalbumin injection, mice were sacrificed and bled for compound concentration monitoring, and spleens were removed for BTK occupancy measurements. The thickness of the injected control and anti-ovalbumin IgG skin sites was measured using a digital caliper, and then the thickness of the anti-ovalbumin IgG injection site minus the saline control site was calculated for all was calculated for mice in the treatment group.

The effect of LOU064 treatment on skin swelling in mice, administered as a single oral (p.o.) nanosuspension gavage at 3, 10, 30 and 100 mg/kg, is shown in Figure 3. Compared to vehicle-treated mice, LOU064 administered 2 hours before the time of Arthus response induction demonstrated a dose-related reduction in skin swelling response at the 3 hour time point. Inhibition of the Arthus response was statistically significant at 73.0%±14.6 and 61.2%±14.5 at the two high doses of 30 and 100 mg/kg, respectively.

Analysis of LOU064 levels in blood Blood samples were collected and compound measurements were performed as indicated. A structurally similar internal standard mixed with acetonitrile (4 volumes) was added to the blood sample and centrifuged at approximately 4000 rpm (4°C). The supernatant was then transferred to a microtiter plate. An aliquot of each sample was injected into the LC-MS/MS system for determination of the concentration of the parent molecule. The concentration of LOU064 present in mouse blood 5 hours after LOU064 administration is shown in Table 2.

BTK occupancy analysis:
For BTK occupancy in the spleen, experiments were performed as described in the PCA Examples. For lung BTK occupancy, the organ was perfused with saline and blood removed in the same manner as for the spleen (except that the lysis buffer volume was 500 μl), followed by the complete trachea-containing Lysates were prepared from the lungs. Lung lysates were then analyzed for free BTK in a separate ELISA. This consisted of a capture step with anti-BTK (Cell Signaling Technologies, #8547, no carrier). The captured BTK protein was then incubated with 1 μM covalently biotinylated BTK probe for 1 hour at room temperature. The BTK-conjugated biotinylated probe was combined with a streptavidin-HRP conjugate (Cell Signaling Technologies, #3999, used at a dilution of 1:1'000) and a chemiluminescent substrate (Supersignal ELISA Pico, Thermo Scientific, #37070). detected by did. Luminescence values were corrected for ELISA background readings from control samples measured in the absence of BTK capture antibody for total BTK ELISA and in the absence of probe for BTK binding ELISA, respectively. Relative BTK occupancy was calculated for each sample as the ratio of free BTK to total BTK (signal of covalently biotinylated probe-bound BTK): R = free BTK/total BTK. Individual Ri values were then normalized to the vehicle group and expressed as percent occupancy: (mean Ri vehicle group - Ri)/(mean Ri vehicle group) ^* 100%.

Figure 4 shows relative BTK occupancy in the spleen 5 hours after oral administration of LOU064. A dose-dependent increase in BTK occupancy was observed, with 68.1% ± 10.0 for 3 mg/kg, 82.1% ± 2.92 for 10 mg/kg, and 91.3% ± 3.0 for 30 mg/kg. An average BTK occupancy of 99.3%±0.7 was achieved for 62 and 100 mg/kg.

In subsequent studies, we evaluated the duration of pharmacological action of LOU064 on the skin. When the Arthus reaction was elicited at the same time point as in the previous study, 2 hours after oral administration of 30 mg/kg LOU064, inhibition of skin swelling was maximal at 65.7% (±14.6). Met. At this point, the effects were in a similar range to previous trials. When the Arthus response was elicited at a later time point, it was revealed that the pharmacological effects of LOU064 in the skin returned to the levels of the vehicle group by the 45 hour time point (Figure 5).

From the same animals, BTK occupancy in the spleen and lungs was analyzed at the termination point (3 hours after triggering the Arthus response). BTK occupancy in the spleen and lung followed a very similar kinetics compared to the pharmacological effects on skin swelling (Figure 6).

Compound exposure was assessed at the first time point after a single dose of 30 mg/kg LOU064 (Table 3).

Conclusion:
This experiment demonstrated the effects of LOU064 in murine RPA, a model of delayed cutaneous anaphylaxis mediated by IgG immune complexes and inflammatory FcγRs. Oral treatment with a single dose of LOU064 at 3, 10, 30 and 100 mg/kg 2 hours before induction of RPA responses dose-dependently reduced skin swelling 3 hours after immune complex challenge. Skin swelling inhibition was statistically significant at both the 30 and 100 mg/kg doses. Blood concentrations of LOU064 5 hours after oral administration increased with dose and showed some overproportionality. It is unclear whether this limited proportional excess reflects changes in Tmax or AUC. Splenic BTK occupancy measured 5 hours after administration showed a dose-dependent increase and reached a maximal level. At the two lower doses of 3 and 10 mg/kg, spleen occupancy appeared to exceed the effect on skin swelling. This may reflect the slightly slower target occupancy kinetics after a single dose in the less perfused skin compared to the highly perfused spleen. The pharmacological effect of LOU064 after a single dose of 30 mg/kg was maximal when the Arthus reaction was elicited 2 hours after oral administration. When the Arthus response was evoked at a later time point, the effect diminished and reached a level similar to the vehicle group at 45 hours post-dose. The baseline drift in skin swelling inhibition towards the final time point may be due to the increased response to Arthus challenge across groups over time. The vehicle group was measured on day 1, along with the 2 and 5 hour compound groups. Over the same time course, BTK occupancy was monitored in the spleen and lungs. In both tissues, BTK occupancy followed a very similar kinetics compared to pharmacological effects on skin swelling. In the absence of a sufficiently sensitive method to measure BTK occupancy in the skin, we speculate that cutaneous BTK occupancy following a single oral administration of LOU064 follows similar kinetics to spleen occupancy and skin pharmacology. can be done. In conclusion, LOU064 was demonstrated to significantly and dose-dependently inhibit skin swelling in the murine reverse passive Arthus model after a single oral administration.

Example 3: Ovalbumin-induced anaphylaxis mouse model This experiment was performed to examine the anti-inflammatory effects of LOU064 (10 mg and 30 mg/Kg) in OVA-sensitized mice injected with polyinosine-polycytidylic acid (poly I:C). I went to

animal:
Male Balb/c mice (20-30 g, Charles Rivers UK Ltd) were housed in five cages for 7 days prior to the start of the study and subjected to a 12:12 hour light/dark cycle. Mice were fed standard mouse chow and had water ad libitum.

Allergen exposure:
Mice were actively sensitized with ovalbumin (15 μg, subcutaneous (s.c.)) and 25 μL of Imject Alum on days 0, 7, and 14. To induce a local inflammatory response in the lungs, mice were treated on days 21-24 with 1% w/v in phosphate-buffered saline (PBS) produced by an ultrasound nebulizer (Aerogen) for 20 minutes. Repeated exposure to ovalbumin aerosol. 16 hours after the last exposure to OVA on day 24, polyinosine-polycytidylic acid (poly I:C, 100 μg/animal) or vehicle (PBS) was combined with ketamine (100 mg/Kg, i.p.) ) and xylazine (10 mg/Kg, intraperitoneal (i.p.)) and delivered intratracheally using a Microsprayer (model IA-1C) with an FMJ-250 high-pressure syringe (Penn-Century).

LOU064 and vehicle treatment:
Mice were administered LOU064 or vehicle (0.5% Tween 80/0.5% methylcellulose (400 cP)/99% water) orally (p.o.) twice daily (B.I.D.). , then a single dose of vehicle (67% PEG200/33% PBS) was given 1 hour before Poly I:C.

Bronchoalveolar lavage (BAL) and cell counting:
Twenty-four hours after the last OVA challenge, blood samples were collected by venipuncture into pre-chilled Li Hep tubes. Plasma was prepared by gently mixing each sample, keeping it on wet ice for up to 15 minutes, and then centrifuging (1500 g, 10 minutes at 4° C.). Each sample was aliquoted and stored at -80°C until shipping. Immediately after blood collection, animals were sacrificed by pentobarbital overdose. The trachea was then separated by a midline incision in the neck and separation of the muscle layers. A small incision was made in the trachea and a plastic cannula was inserted and secured in place with sutures. The airways were then lavaged by flushing the lungs with 0.5 mL of phosphate buffered saline. This procedure was repeated until the recovered volume was 1.6 mL. The isolated BALF was then centrifuged at 1500 rpm for 10 minutes at 4°C and the supernatant was aliquoted (400 μL) at -80°C for any further cytokine analysis. The cell pellet was then resuspended in 1.6 mL of phosphate buffered saline and BAL cells were analyzed for total and differential numbers. Total and differential cell counts of BAL fluid samples were measured using an XT-2000iV analyzer (Sysmex). Differently classified cell types were eosinophils (Figure 8), neutrophils (Figure 9), or mononuclear cells (macrophages (Figure 10) and lymphocytes (Figure 11)).

Conclusion: Treatment with LOU064 (10 mg/kg, 30 mg/Kg) significantly reduced the number of cells involved in pulmonary anaphylaxis (eosinophils, basophils, macrophages and lymphocytes).

Example 4: Inhibition of FcεR-induced mast cell degranulation in LAD2 cells Rationale and Methods: The human mastocytosis cell line LAD2 expresses FcεRI and upon cross-linking of the receptor, cells degranulate and release β-tryptase. and releases inflammatory mediators such as hexosaminidase (Wernersson et al. 2014, Immunology; 14(7):478-94). The assay involves 4-hydroxy-3-iodo-5-nitrophenylacetic acid (NIP) haptenated bovine serum albumin (BSA) and NIP-specific chimeric IgE antibody JW8 (Neuberger, M.S. et al. (1985) , Nature 314(6008), pp 268-70.doi:10.1038/314268a0). LAD2 cells were sensitized with JW8 IgE antibody and then incubated with serial compound dilutions for 30 minutes at 37°C. Degranulation was then caused by adding haptenated NIP-BSA to cross-link the FcεR. After 1 hour, supernatants were collected and analyzed for β-tryptase levels.

Results: Consistent with its potent activity in basophil activation assays, LOU064 inhibited IgE/FcεR-induced mast cell degranulation in LAD2 cells with an IC50 of 7.0 nM ± 2.6 (n = 3). showed strong inhibition.

Example 5: Inhibition of FcεR-induced degranulation of peripheral blood mononuclear cell (PBMC)-derived mast cells Rationale and Methods: Primary human mast cells were obtained from CD34-positive progenitor cells isolated from PBMC ((Neuberger, M. Blood from healthy volunteers was donated with informed consent and sent to the Swiss Human Research Act and responsible ethical committee approval (Ethikkommission Nordwest-und Zentralschweiz). Briefly, CD34-positive cells were isolated from peripheral blood by positive selection, SCF, IL -6 and IL-3. After 6 weeks of differentiation culture, mast cells were collected and phenotypically characterized for expression of c-Kit (CD117) and FcεRI. , based on NIP-haptenated BSA and NIP-specific chimeric IgE antibody JW8 (described in RD-2013-00412). Mast cells were sensitized with JW8 IgE antibody and then incubated for 30 min at 37°C. Incubated with serial compound dilutions. Degranulation was then caused by adding haptenated NIP-BSA to cross-link the FcεR. After 1 hour, supernatants were collected and analyzed for β-tryptase levels. .

Results: Similar to other FcεR inhibitory activities, LOU064 potently and completely blocked in vitro degranulation of primary human PBMC-derived mast cells with an IC50 of 5.7 nM±2.4 (n=7 donors).

Example 6: Inhibition of skin-derived human mast cells.
Rationale and Methods: Skin tissue was used as a source of primary human tissue mast cells. Surgical skin waste samples were provided with informed consent and were collected at the University Hospital Base in accordance with the Swiss Human Research Act and approval by a responsible ethics committee (Ethikkommission Nordwest und Zentralschweiz). Collected by l. Skin tissue was dissociated and intact mast cells were prepared according to the protocol of Kulka and Metcalfe (current protocol in Kulka et al. 2010, Immunology; SUPPL. 90:1-11). Isolated mast cells were phenotypically characterized and used for degranulation assays as described above ((Neuberger, M.S. et al. (1985), Nature 314(6008), pp 268-70 .doi:10.1038/314268a0). Mast cells were sensitized with JW8 IgE antibody and then preincubated with serial compound dilutions for 30 min at 37°C. Degranulation was then performed using haptenized NIP. - BSA was added to cross-link the FcεRI. After 30 minutes, the supernatant was collected and analyzed for histamine using an HTRF-based immunoassay (Cisbio Bioassays).

Results: Similar to its activity in previous types of FcεRI-induced cell signaling, LOU064 potently inhibited histamine release from human primary skin-derived mast cells with an IC50 of 16.5 nM ± 5.0 (n = 2 donors). inhibited.

The in vitro intracellular efficacy of LOU064 evaluated across several cell types in Examples 4-6 supports its use in allergic diseases induced by the FcεR pathway.

Example 7: LOU064 Dosing (Rationale)
In a mouse PCA model, LOU064 was demonstrated to be effective in inhibiting FcεR responses in cutaneous mast cells at doses as low as 3 mg/kg (Figure 1). Splenic BTK occupancy, which may be a more relevant biomarker for predicting efficacy in the prevention and/or treatment of IgE-induced allergic reactions (especially food allergic reactions), showed almost complete occupancy at 10 and 100 mg/kg. Show rate.

It was further demonstrated that in mice, BTK occupancy in the spleen and lung followed very similar kinetics (Figure 6).

It was also demonstrated that LOU064 was effective in reducing skin swelling in the murine RCA model, primarily at high doses (73% inhibition of Arthus reaction at 30 mg/Kg).

Importantly, it was also demonstrated that LOU064 treatment of mice in the ovalbumin-induced anaphylaxis model resulted in a significant reduction in the number of cells involved in pulmonary anaphylaxis at doses of 10 mg/kg and 30 mg/kg.

All preclinical results support an effective dose for LOU064 in mice of the order of 10 mg/kg. 30 mg/kg was also shown to be effective in mice.

Additional BTK occupancy in the human spleen was predicted using a translational PK/PD model to further aid dose selection.

Prediction of BTK occupancy using translational PK/PD model for LOU064 BTK occupancy in blood is not a useful biomarker for dose selection due to LOU064 pharmacological properties (irreversible binding). It reaches full occupancy even at low doses before showing pharmacological activity by other biomarkers (CD63, CD203c, skin prick test). Occupancy in the tissue may be more representative of the expected effectiveness of LOU064.

Purpose The purpose of this analysis was to characterize the pharmacokinetics (PK) of LOU064 in healthy volunteers, using a previously developed translated target occupancy model, over a range of doses and dosing regimens (twice daily). The objective was to simulate BTK occupancy in human spleen/tissue over a period of time (B.I.D. vs. once daily (QD)).

Data Kaul et al. (2021), including 102 patients, were used in this analysis.

Methods A translational target occupancy model to simulate BTK occupancy in spleen/tissue was developed using a two-step approach.

In the first step, a population PK model is developed as described by Kaul et al. (2021) was established to illustrate the LOU064 PK data from a phase I clinical trial. In the second step, parameter estimates from the population PK model were used in a BTK occupancy model to predict BTK occupancy in blood and spleen/tissue. Finally, the BTK occupancy model was used to predict BTK occupancy in the spleen/tissue at different doses and for different dosing regimens (once daily (QD), twice daily (B.I.D.)). .

Results The population PK model was developed by Kaul et al. (2021) to describe the intermediate PK from a phase I clinical trial. To address changes in clearance after repeated administration of doses less than 50 mg (lower clearance at steady state on day 12 compared to day 1 with no difference at high doses), the clearance was Modeled as a function of exponential time decay for doses below 50 mg and constant clearance for doses above 50 mg. In general, the resulting population model explained the PK data to some extent.

The PK parameter estimates were used in a translated BTK occupancy model to simulate BTK occupancy at steady state. BTK occupancy simulation showed that twice daily (B.I.D.) dosing was more effective than once daily (QD) dosing of the same dose to achieve higher BTK occupancy. (in a trough or on average over a 24 hour period).

For selected dosing frequencies in once daily (QD) and twice daily (B.I.D) regimens, the trough and average steady state BTK occupancy over a 24 hour period was 10 mg once daily; FIG. 14A (Trough of BTK occupancy at steady state over 24 hours) and FIG. 14B (Average over 24 hours of BTK occupancy at steady state) for the 35 mg, 100 mg and twice daily 10 mg, 25 mg and 100 mg regimens, respectively. is shown. Both figures demonstrate that daily doses of up to 200 mg (100 mg twice daily (B.I.D.)) may be required to achieve trough BTK occupancy ≧80% in peripheral target tissues. shows.

Simulations were performed to compare different dosing regimens. A comparison of simulated splenic BTK occupancy at steady state of 100 mg twice daily (B.I.D.) vs. 100 mg once daily (QD) over time is shown in FIG. The graph shows that the occupancy from twice daily (B.I.D.) dosing is higher and less variable compared to once daily (QD) dosing, as expected from the basic principles. Show that.

Conclusion:
BTK occupancy simulation showed that twice daily (B.I.D.) dosing was more effective than once daily (QD) dosing of the same dose to achieve higher BTK occupancy. (in a trough or on average over a 24 hour period).

Based on a conversion model between animals and humans (Journal of basic and clinical pharmacy, 7(2), 27-31), the calculated human equivalent dose (HED) for 30 mg/kg is The calculated human equivalent dose (HED) for the minimum effective dose of 10 mg/kg is approximately 56 mg for a 70 Kg person (Nair, A.B., & Jacob, S. 2016).

Finally, a predictive model of splenic BTK occupancy in humans suggests that twice-daily (b.i.d.) administration is more effective than once-daily (b.i.d.) administration of the same dose to achieve higher BTK occupancy. QD) was shown to be more effective than administration (Fig. 13). Therefore, 25 mg b. i. The dose of LOU064 in d is the lowest human effective dose, 100 mg b. i. d. Doses of 0.25% are also shown to be effective in humans.

Example 8: Clinical trial peanut allergy phase 2
Three dosing regimens (LOU064 10 mg twice daily (B.I.D.), 25 mg twice daily (B.I.D.) and 100 mg twice daily (B.I.D.) in adult patients with peanut allergy indicated. A randomized, double-blind, placebo-controlled, 4-week study evaluating B.I.D.).

This "Peanut Study" was a double-blind, placebo-controlled, oral food challenge (DBPCFC) of 600 mg of peanut protein after 4 weeks of treatment in the proportion of patients with no objective allergic reaction to LOU064 compared to placebo. (10 mg twice a day (B.I.D.), 25 mg twice a day (B.I.D.), and 100 mg twice a day (B.I.D.)) ing. Additionally, we evaluated the proportion of patients treated with LOU064 25 mg twice daily (B.I.D.) for only 1 week but who similarly did not have an objective allergic reaction to 600 mg of peanut protein DBPCFC. and will be compared with a placebo. Secondary endpoints for all treatment arms include response to 1000 mg and 3000 mg peanut protein.

Example 9: Clinical trial peanut allergy phase 3
A randomized, double-blind, placebo-controlled, 10-18 week study evaluating LOU064 in approximately 300 adults and adolescents (12-55 years of age) with indicated peanut allergies. The peanut study was a double-blind, placebo-controlled, oral food challenge (DBPCFC) of levels of 600 mg, 1000 mg, and 3000 mg peanut protein in the proportion of participants with no objective allergic reaction at 1 or 2 weeks. , will evaluate the efficacy of LOU064 compared to placebo.

Example 10: Clinical Trial Milk and Egg Allergy A randomized, double-blind, placebo-controlled study evaluating LOU064 in approximately 450 adult and adolescent participants aged 12-55 years with indicated nut, milk, or shrimp allergies. Control, 10-18 week basket trial.

A basket test evaluating nut, milk and shrimp allergens objectively tested DBPCFC at multiple levels of 1'000 mg (non-cumulative) and 3'000 mg (non-cumulative) nut/milk/shrimp protein at 1 or 2 weeks. The efficacy of LOU064 compared to placebo is evaluated by the percentage of patients who do not have a typical allergic reaction.

Example 11: 100 mg film-coated tablets Below, preferred pharmaceutical compositions (film-coated tablets) are shown.

Example 12: 25 mg film-coated tablets Below, preferred pharmaceutical compositions (film-coated tablets) are shown.

Example 13: 10 mg film-coated tablets Below, preferred pharmaceutical compositions (film-coated tablets) are shown.

Example 14: Safety of LOU064 The safety of LOU064 has been demonstrated as a Phase I and Phase II drug in patients suffering from indications other than MS, particularly chronic spontaneous urticaria (CSU) and Sjögren's syndrome (SjS). Kinetics and clinical pharmacology were tested in healthy subjects studies and Phase II/III clinical trials.

Short-term safety of LOU064 in a Phase I clinical trial. Short-term safety of LOU064 at 100 and 200 mg twice daily (b.i.d.) for days was demonstrated in a Phase I clinical trial (Kaul, M. et al. (2021). Remibrutinib (LOU064): A selective potent oral BTK inhibitor with promising clinical safety and pharmacodynamics in a randomi zed phase I trial.Clinical and Translational Science.10.1111/cts.13005).

Summary of safety in Phase 2b study (extension phase) in CSU subjects (interim results)
In a 52-week open-label extension study to evaluate the long-term safety and tolerability of LOU064 in eligible subjects with CSU who participated in the Phase 2b study, the doses used were 100 mg twice a day (b.i.d.).

Safety signals were observed based on an interim analysis of 100 subjects given at least one dose of LOU064 with a median exposure of 17.86 weeks (range: 2.9 weeks to 44.7 weeks). There wasn't. At cutoff, 93 subjects (93%) were ongoing and 7 subjects had discontinued the study; none of the discontinuations were due to adverse events. Table 4 provides a summary of the safety observed in the Phase 2b study up to the cutoff date for interim analysis.

Fifty-eight subjects (58%) had at least one treatment-emergent AE. The majority of AEs were non-serious, did not lead to treatment discontinuation, and were mild in severity. The most frequently affected SOCs were infections and parasitic diseases (14%), followed by skin and subcutaneous tissue disorders (13%), with no trends regarding specific adverse events. The most common adverse event terms (≥2%) were headache (6%), diarrhea (4%), dizziness (3%) and gastroenteritis (3%); bleeding events (Bleeding SMQ Broad and Platelet) (defined as events under PT, including aggregation abnormalities, platelet aggregation reduction, platelet aggregation inhibition, platelet dysfunction, platelet function test abnormalities, and platelet toxicity) or events under SOC Blood and Lymphatic Disorders are not reported. There wasn't. Three SAEs were reported: ovarian cyst, chest pain, and appendicitis; none were considered related to study drug.

Conclusions from the Phase 2b study and corresponding open-label extension study Taken together, there were no safety findings in the Phase 2b study across all doses evaluated. Additionally, in a corresponding CSU extension study using LOU064 100 mg twice daily (b.i.d.) in an open-label manner, safety signals were observed in 100 patients enrolled as of 31-Aug-2020. Not observed in subjects. The highest dose offered, 100 mg LOU064 twice daily (b.i.d.), was considered well tolerated and had a favorable safety profile.

Summary of Safety in Phase 2b Study (Extension Phase) in CSU Subjects (Interim Results/Patients with Median Exposure of 35.14 Weeks) At a dose of 100 mg twice daily (b.i.d.) , conducted a new interim analysis in the 52-week open-label extension study described above to evaluate the long-term safety and tolerability of LOU064 in eligible subjects with CSU who participated in the Phase 2b study. (1:1:1:1:1:1:1) remibrutinib 10 mg qd (once daily), 35 mg qd, Randomized, double-blind, placebo in adult patients with CSU given 100 mg qd, 10 mg bid (twice daily), 25 mg bid, or 100 mg bid or placebo for up to 12 weeks (wks) (NCT03926611) Comparisons were made with safety results in the control Ph2b core study (Table 5).

In long-term exposure to ES (median 35.14 weeks, N=183), the proportion of patients with at least one adverse effect (AE) to remibrutinib treatment (57.4% [n=105]) was was similar to CS (as indicated by any remibrutinib dose) (58.1% [n=155]; median 12.14 weeks, N=267). In ES, there were 4 serious adverse effects (SAEs), 6 AEs leading to treatment discontinuation and death. The incidence of AEs by system system classification (SOC) reported in ES and CS was similar: infections and parasitic diseases (23.0% and 24.0%), followed by skin/subcutaneous tissue disorders. (17.5% and 16.9%) (Table 5). The incidence of AEs reported by base term was comparable in ES and CS, with headache (6.6% and 9.7%) being the most frequent. The occurrence of AESI in ES was consistent with CS, including infection (23%), bleeding (4.4%) and cytopenias (0.5%). Newly occurring significant aminotransferase increases were associated with ES (isolated ALT >3 × ULN, normalized within 4 weeks in one patient who discontinued early for personal reasons) and CS ( ALT > 5 x ULN in 1 patient) normalized to treatment. Analysis of laboratory parameters revealed no significant safety concerns, and no clinically significant changes in vital signs were observed. There were no significant ECG findings or QT >500ms demonstrated in any patient.

Conclusions Remibrutinib showed a favorable safety profile across the entire dose range, with no new safety signals observed over longer periods of exposure to doses of 100 mg bid for up to 52 weeks in patients with CSU.

Example 15: Evaluation of modulation of immune responses to three different types of vaccines by simultaneous and intermittent administration of remibrutinib in healthy subjects

Study Design Overall Design This randomized, double-blind, placebo-controlled study has a parallel group comparison design. Approximately 90 healthy female and male participants of no childbearing potential were enrolled in 3 trials to achieve a minimum of 72 evaluable completers considering an estimated discontinuation rate of up to 20%. Randomize into one of the treatment groups. The study will consist of a 28-day screening period, a 43-day treatment period, followed by a study completion assessment (Day 57) within two weeks after the last study drug dose. A safety follow-up call will occur approximately 30 days after the last study drug dose (Day 73). Participants are settled from day -1 to day 1 and from day 14 to day 17. In total, the maximum study period for each participant is approximately 85 days.

Simultaneous and intermittent remibrutinib treatment scenarios for influenza/impact of Pneumovax® 23 and Immucothel® is evaluated versus placebo.

Study Implementation Screening and Baseline Participants who meet eligibility criteria at screening will undergo a baseline assessment on Day -1. All baseline safety assessment results must be available before the first dose. At baseline, participants will be randomly assigned to one of three treatment groups described below.

Treatment All participants received study drug (remibrutinib 100 mg or placebo twice daily (b.i.d.)) from day 1 to day 42, and for the end of the treatment visit on day 43. Return to the clinic. All participants will also receive quadrivalent influenza vaccine, PPV-23 vaccine and KLH neoantigen vaccine on day 15. Vaccination should occur 3 hours after study drug administration.

During clinical visits and settlements (Days -1 to 1 and 14-17), participants will be administered study drug by study personnel in the clinic. Upon discharge from clinical visits during the treatment period, study medication will be given to participants for self-administration at home, along with a medication diary.

Safety evaluations will include physical examination, ECG, vital signs, standard laboratory evaluations (hematology, blood chemistry, urinalysis) adverse events and serious adverse event monitoring.

Multiple blood samples were obtained from all participants on days 8, 15, and 36 to assess remibrutinib pharmacokinetics.

Group A (concurrent remibrutinib treatment):
Participants received placebo (b.i.d.) on days 1-7 followed by a PK/PD steady state prior to administration of the three vaccines on day 15. , treatment with remibrutinib (100 mg twice daily (b.i.d.)) will be administered on study days 8-15. Participants will continue to receive remibrutinib (100 mg twice daily (b.i.d.)) until day 42.

Group B (intermittent remibrutinib treatment):
Participants were treated with remibrutinib 100 mg twice daily (b.i.d.) on days 1-7, followed by placebo on days 8-28 to achieve PK/PD steady-state conditions. (b.i.d.) and will receive three vaccines on day 15. Treatment with remibrutinib 100 mg twice daily (b.i.d.) will be resumed on days 29-42.

Group C (Placebo):
Participants in Group C will receive a placebo (b.i.d.) on days 1-42 and receive three vaccines on day 15 under placebo conditions.

Key Eligibility Criteria Signed informed consent must be obtained prior to participation in the study.
- Healthy, mildly obese, or otherwise healthy male and non-fertile female participants aged 18-55 (inclusive).
- Participants should be in good health as determined by medical history, physical examination at screening and baseline visits, vital signs, ECG, and laboratory tests, as indicated.
- At screening and baseline, vital signs (systolic and diastolic blood pressure and pulse rate) are assessed in the sitting position and again in the standing position (if required by the assessment schedule). Sedentary vital signs (after sitting for 3 minutes) should be within the following ranges:
・Eardrum temperature of 35.0-37.5℃.
- Systolic blood pressure (SBP) between 90 and 139 mmHg (including endpoints).
Diastolic blood pressure (DBP) between 50 and 89 mmHg (including endpoints).
- Pulse rate between 45 and 90 bpm (including endpoints).
- Participants must weigh at least 50 kg to participate in the study and must have a body mass index (BMI) within the range of 18-34.9 kg/m2.
- Participants must be willing to remain in the clinical setting as required by the protocol and follow the requirements/instructions outlined in the ICF.
- Be able to read, speak, and understand the local language in order to understand and comply with exam requirements.

Key Exclusion Criteria: Use of other study drugs within 1.5 half-lives or 30 days before first dose, whichever is longer.

2. Current evidence or history of clinically significant ECG abnormalities or family history (grandparents, parents, and siblings) of long QT syndrome or other abnormalities in cardiac conduction, torsade de pointes (TdP) (e.g., heart failure, history of additional risk factors (hypokalemia) and/or known medical history or current clinically significant arrhythmia. Abnormal ECG defined as PR > 220 msec, QRS complex > 120 msec, QTcF > 450 msec for men and women, or any other morphological changes other than early repolarization, non-specific ST or T wave changes.

3. Treated or untreated malignancy of any organ system (other than localized basal cell carcinoma of the skin or cervical cancer in situ) within the past 5 years, with or without evidence of local recurrence or metastasis. Medical history or presence.

4. Any disease in any system subcategory, including (but not limited to) cardiovascular, pulmonary, metabolic, hepatic, renal, hematologic, endocrine, neurological, or psychiatric disease that has not resolved within two weeks prior to the first dose. History or presence of clinically significant disease.

5. Hypersensitivity to remibrutinib or drugs from the same compound class or its excipients.

6. For use of Pneumovax 23, influenza or KLH vaccines, including any acute infection, fever, or hypersensitivity reactions or known hypersensitivity to any relevant components of the vaccine administered in this study (e.g. eggs or shellfish/KLH) Any contraindications.

7. Vaccination history for the 2022-2023 seasonal influenza vaccine or known clinical diagnosis of influenza infection during the 2022-2023 influenza season prior to enrollment.

8. History of past exposure or immunization with KLH.

Claims (41)

BTK inhibitors, e.g. irreversible BTK inhibitors, e.g. LOU064 or a pharmaceutically acceptable salt thereof. LOU064 or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the one or more allergens include or are food allergens. LOU064 or a pharmaceutically acceptable salt thereof for use according to claim 2, wherein the food allergen is selected from peanuts, nuts, milk, wheat, eggs, soybeans, sesame, seafood, especially peanuts. . 4. LOU064 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1, 2 or 3, wherein LOU064 is administered at a dose of about 20 mg to about 200 mg daily. 5. LOU064 or a pharmaceutically acceptable salt thereof for use according to claim 4, wherein LOU064 is administered at a dose of about 10 mg twice a day to about 100 mg twice a day. 6. LOU064 or a pharmaceutically acceptable salt thereof for use according to claim 5, wherein LOU064 is administered at a dose of about 10 mg twice a day. 6. LOU064 or a pharmaceutically acceptable salt thereof for use according to claim 5, wherein LOU064 is administered at a dose of about 25 mg twice a day. 6. LOU064 or a pharmaceutically acceptable salt thereof for use according to claim 5, wherein LOU064 is administered at a dose of about 100 mg twice a day. LOU064 or its Pharmaceutically acceptable salts. 10. LOU064 or a pharmaceutically acceptable salt thereof for use according to claim 9, wherein LOU064 is administered for a period of up to 18 weeks, such as 4, 10, 12, 16 or 18 weeks. LOU064 or its pharmaceutical composition for use according to any one of claims 1 to 8, wherein LOU064 is administered for a long period of time, for example for more than 6 months, preferably for one year or more than one year. Acceptable salt. 12. LOU064 or a pharmaceutically acceptable salt thereof for use according to claim 10 or 11, wherein LOU064 is administered as monotherapy. LOU064 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 12, wherein LOU064 is not administered simultaneously with a strong inhibitor of CYP3A, such as a strong inhibitor of CYP3A4. . LOU064 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 11 or 13, wherein LOU064 is co-administered with a therapeutic agent. LOU064 is co-administered with corticosteroids and/or immunosuppressants (e.g. inhaled corticosteroids), leukotriene receptor antagonists (LTRA), short-acting beta agonists (SABA) or long-acting beta agonists (LABA) LOU064 or a pharmaceutically acceptable salt thereof for the use according to claim 14. 14. According to any one of claims 1 to 11 or 13, wherein LOU064 is co-administered with oral immunotherapy (OIT), sublingual immunotherapy (SLIT), transcutaneous immunotherapy (EPIT), preferably with OIT. A BTK inhibitor, such as LOU064 or a pharmaceutically acceptable salt thereof, for use in. BTK for use according to claim 16, wherein LOU064 is an adjunct to oral immunotherapy (OIT), sublingual immunotherapy (SLIT), transcutaneous immunotherapy (EPIT), preferably OIT. Inhibitors such as LOU064 or a pharmaceutically acceptable salt thereof. 18. A BTK inhibitor, such as LOU064 or a pharmaceutically acceptable salt thereof, for use according to claim 16 or 17, wherein the oral immunotherapy is a peanut protein (such as Palforzia™). BTK inhibitor for use according to any one of claims 16 to 18, wherein LOU064 is administered starting at least 2 days (eg at least 2 to 14 days) before administration of the oral immunotherapy. , such as LOU064 or a pharmaceutically acceptable salt thereof. 20. A BTK inhibitor, such as LOU064, or a pharmaceutically acceptable salt thereof, for use according to claim 19, wherein said BTK inhibitor, such as LOU064, is administered during the titration phase of said immunotherapy treatment. BTK inhibitor, such as LOU064 or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1 to 20, wherein said method is the prevention of IgE-induced allergic reactions. BTK inhibitor, e.g. Salt allowed in. LOU064 or its pharmaceutical composition for use according to claim 21 or 22, wherein LOU064 achieves maximal protection after a minimum of 2 days (eg after 2-14 days, preferably after 2-7 days) of treatment. Salt allowed in. The patient meets the following criteria:
(e) male and female patients, 6 years of age or older (e.g., 6-11 years, 12-17 years, or 18-55 years);
(f) Confirmed history of allergies to foods including, but not limited to, peanuts, nuts, wheat, eggs, milk, soy, seafood;
(g) positive allergen-specific IgE (e.g., peanut sIgE ≧6 kUA/L at screening); and (h) positive skin prick test for an allergen to which the patient is allergic (e.g., compared to negative control). , defined as mean diameter (longest diameter and midpoint orthogonal diameter) ≧4 mm)
LOU064 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 23, selected according to one or more of: LOU064 or a pharmaceutically acceptable drug thereof for use according to any one of claims 1 to 24, wherein the patient is an adult patient (18 years of age or older) or an adolescent (12 to 17 years of age). salt. LOU064 or a pharmaceutically acceptable drug thereof for use according to any one of claims 1 to 24, wherein the patient is a child aged 2 to 11 years, such as 2 to 5 years or 6 to 11 years. salt. At least one of the following applies:
up to 4 weeks (e.g. 1 week, or 2 weeks, or 3 weeks or 4 weeks) after treatment with LOU064;
d. At least 90% of treated patients do not exhibit allergic reactions upon dietary loading of 600 mg peanut protein;
e. At least 90% of treated patients do not exhibit allergic reactions upon dietary loading of 1000 mg peanut protein;
f. LOU064 or a pharmaceutically acceptable form thereof for use according to any one of claims 1 to 26, wherein at least 80% of the treated patients do not show an allergic reaction upon a dietary challenge of 3000 mg of peanut protein. salt. LOU064 or its pharmaceutical composition for use according to any one of claims 1 to 27, wherein the patient achieves a reduction from baseline in total domain score FAQLQ of 0.45 to 0.5. Salt allowed in. LOU064 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 28, wherein said patient achieves a reduction from baseline in total domain score FAIM. The observed difference in response rate between treated and untreated patients in a double-blind, placebo-controlled food challenge of 600 mg of allergen (e.g., peanut allergen) is greater than 35%, where the response rate is greater than 35%; , 600 mg of oral food challenge. By week 12 or week 24 of treatment, levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lipase have decreased by 10% compared to baseline levels at the beginning of treatment. 31. LOU064 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 30, which does not vary by more than 30%. LOU064 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 31, wherein LOU064 is administered in the form of a suitable oral pharmaceutical formulation comprising nanosized particles of LOU064. 33. The LOU064 is administered in the form of a suitable oral pharmaceutical formulation comprising nanosized particles of LOU064 having an average particle size of about 50 nm to about 750 nm as measured by PCS. LOU064 or a pharmaceutically acceptable salt thereof for use in. LOU064 or its pharmaceutical composition for use according to any one of claims 1 to 33, wherein LOU064 is administered in the form of a suitable oral pharmaceutical formulation comprising LOU064 and a binder in a weight ratio of about 2:1. Salt allowed in. Use according to any one of claims 1 to 34, wherein LOU064 is administered in the form of a suitable oral pharmaceutical formulation comprising LOU064, binder and surfactant in a weight ratio of about 2:1:0.08. Its LOU064 for. 34. LOU064 for use according to any one of claims 1 to 33, wherein LOU064 is administered in the form of a suitable oral pharmaceutical formulation comprising LOU064 and a binder in a weight ratio of about 1:1. 37. According to any one of claims 1 to 34 or 36, wherein LOU064 is administered in the form of a suitable oral pharmaceutical formulation comprising LOU064, a binder and a surfactant in a weight ratio of about 1:1:0.05. LOU064 for use. 38. LOU064 is administered in the form of a suitable oral pharmaceutical formulation comprising LOU064, polyvinylpyrrolidone-vinyl acetate copolymer as binder and sodium lauryl sulfate as surfactant. LOU064 for use. When LOU064 is measured at a temperature of about 25° C. and an X-ray wavelength, λ, of 1.5405 Å, it has 7.8 ± 0.2° 2θ, 9.2 ± 0.2° 2θ, 12.0 ± 0. 2°2θ, 13.6±0.2°2θ, 15.6±0.2°2θ, 16.0±0.2°2θ, 17.8±0.2°2θ, 18.3±0. 2°2θ, 18.7±0.2°2θ, 19.2±0.2°2θ, 19.9±0.2°2θ, 22.1±0.2°2θ, 23.4±0. 2°2θ, 23.9±0.2°2θ, 24.8±0.2°2θ, 25.2±0.2°2θ, 25.5±0.2°2θ, 27.2±0. 2° 2θ, and 29.6 ± 0.2° 2θ, characterized by an X-ray powder diffraction pattern containing one or more representative peaks in 2θ , LOU064 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 38. LOU064 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in the treatment or prevention of IgE-induced allergic reactions, preferably LOU064 in a dose of about 10 mg twice a day to twice a day. LOU064 or a pharmaceutically acceptable salt thereof, administered at a dose of about 100 mg. Use of LOU064 or a pharmaceutically acceptable salt thereof for the treatment or prevention of IgE-induced allergic reactions, preferably said LOU064 is administered at a dose of about 10 mg twice a day to about 100 mg twice a day. administered, used.